Azole derivatives and fused bicyclic azole derivatives as therapeutic agents

ABSTRACT

This invention provides certain compounds, methods of their preparation, pharmaceutical compositions comprising the compounds, and their use in treating human or animal disorders. The compounds of the invention are useful as modulators of the interaction between the receptor for advanced glycated end products (RAGE) and its ligands, such as advanced glycated end products (AGEs), S100/calgranulin/EN-RAGE, β-amyloid and amphoterin, and for the management, treatment, control, or as an adjunct treatment for diseases in humans caused by RAGE. Such diseases or disease states include acute and chronic inflammation, the development of diabetic late complications such as increased vascular permeability, nephrdpathy, atherosclerosis, and retinopathy, the development of Alzheimer&#39;s disease, erectile dysfunction, and tumor invasion and metastasis.

STATEMENT OF RELATED APPLICATION

The present application is a divisional application of pending U.S. patent application Ser. No. 11/511,163, filed Aug. 28, 2006, entitled “Azole Derivatives and Fused Bicyclic Azole Derivatives as Therapeutic Agents,” which is a divisional application of U.S. patent application Ser. No. 10/382,203, filed Mar. 5, 2003, entitled “Azole Derivatives and Fused Bicyclic Azole Derivatives as Therapeutic Agents,” now issued as U.S. Pat. No. 7,361,678, which claims priority under 35 U.S.C. §119(e) from U.S. Provisional Application No. 60/361,983, filed Mar. 5, 2002, entitled “Azole Derivatives as Therapeutic Agents,” which are each incorporated by reference in their entireties herein.

FIELD OF THE INVENTION

This invention relates to compounds which are modulators of the receptor for advanced glycated end products (RAGE) and interaction with its ligands such as advanced glycated end products (AGEs), S100/calgranulin/EN-RAGE, β-amyloid and amphoterin, for the management, treatment, control, or as an adjunct treatment of diseases caused by RAGE.

BACKGROUND OF THE INVENTION

Incubation of proteins or lipids with aldose sugars results in nonenzymatic glycation and oxidation of amino groups on proteins to form Amadori adducts. Over time, the adducts undergo additional rearrangements, dehydrations, and cross-linking with other proteins to form complexes known as Advanced Glycosylation End Products (AGEs). Factors which promote formation of AGEs included delayed protein turnover (e.g. as in amyloidoses), accumulation of macromolecules having high lysine content, and high blood glucose levels (e.g. as in diabetes) (Hori et al., J. Biol. Chem. 270: 25752-761, (1995)). AGEs have implicated in a variety of disorders including complications associated with diabetes and normal aging.

AGEs display specific and saturable binding to cell surface receptors on endothelial cells of the microvasculature, monocytes and macrophages, smooth muscle cells, mesengial cells, and neurons. The Receptor for Advanced Glycated Endproducts (RAGE) is a member of the immunoglobulin super family of cell surface molecules. The extracellular (N-terminal) domain of RAGE includes three immunoglobulin-type regions, one V (variable) type domain followed by two C-type (constant) domains (Neeper et al., J. Biol. Chem. 267:14998-15004 (1992)). A single transmembrane spanning domain and a short, highly charged cytosolic tail follow the extracellular domain. The N-terminal, extracellular domain can be isolated by proteolysis of RAGE to generate soluble RAGE (sRAGE) comprised of the V and C domains.

RAGE is expressed in most tissues, and in particular, is found in cortical neurons during embryogenesis (Hori et al., J. Biol. Chem. 270:25752-761 (1995)). Increased levels of RAGE are also found in aging tissues (Schleicher et al., J. Clin. Invest. 99 (3): 457-468 (1997)), and the diabetic retina, vasculature and kidney (Schmidt et al., Nature Med. 1:1002-1004 (1995)). Activation of RAGE in different tissues and organs leads to a number of pathophysiological consequences. RAGE has been implicated in a variety of conditions including: acute and chronic inflammation (Hofmann et al., Cell 97:889-901 (1999)), the development of diabetic late complications such as increased vascular permeability (Wautier et al., J. Clin. Invest. 97:238-243 (1995)), nephropathy (Teillet et al., J. Am. Soc. Nephrol. 11:1488-1497 (2000)), atherosclerosis (Vlassara et. al., The Finnish Medical Society DUODECIM, Ann. Med. 28:419-426 (1996)), and retinopathy (Hammes et al., Diabetologia 42:603-607 (1999)). RAGE has also been implicated in Alzheimer's disease (Yan et al., Nature 382: 685-691, (1996)), erectile dysfunction, and in tumor invasion and metastasis (Taguchi et al., Nature 405: 354-357, (2000)).

In addition to AGEs, other compounds can bind to, and modulate RAGE. In normal development, RAGE interacts with amphoterin, a polypeptide which mediates neurite outgrowth in cultured embryonic neurons (Hori et al., 1995). RAGE has also been shown to interact with EN-RAGE, a protein having substantial similarity to calgranulin (Hofmann et al., Cell 97:889-901 (1999)). RAGE has also been shown to interact with β-amyloid (Yan et al., Nature 389:589-595, (1997); Yan et al., Nature 382:685-691 (1996); Yan et al., Proc. Natl. Acad. Sci., 94:5296-5301 (1997)).

Binding of ligands such as AGEs, S100/calgranulin/EN-RAGE, β-amyloid, CML (N^(ε)-Carboxymethyl lysine), and amphoterin to RAGE has been shown to modify expression of a variety of genes. For example, in many cell types interaction between RAGE and its ligands generates oxidative stress, which thereby results in activation of the free radical sensitive transcription factor NF-κB, and the activation of NF-κB regulated genes, such as the cytokines IL-1β, TNF-α, and the like. In addition, several other regulatory pathways, such as those involving p21ras, MAP kinases, ERK1 and ERK2, have been shown to be activated by binding of AGEs and other ligands to RAGE. In fact, transcription of RAGE itself is regulated at least in part by NF-κB. Thus, an ascending, and often detrimental, spiral is fueled by a positive feedback loop initiated by ligand binding. Antagonizing binding of physiological ligands to RAGE, therefore, is our target for down-regulation of the pathophysiological changes brought about by excessive concentrations of AGEs and other ligands for RAGE.

Thus, there is a need for the development of compounds that antagonize binding of physiological ligands to the RAGE receptor.

SUMMARY OF THE INVENTION

This invention provides substituted benzimidazole compounds. Embodiments of the present invention provide compounds of Formula (I) as depicted below, methods of their preparation, pharmaceutical compositions comprising the compounds, and methods for their use in treating human or animal disorders. Compounds of the invention are useful as modulators of the interaction of the receptor for advanced glycated end products (RAGE) with its ligands such as advanced glycated end products (AGEs), S100/calgranulin/EN-RAGE, β-amyloid and amphoterin. The compounds are useful in a variety of applications including the management, treatment, control, and/or as an adjunct of diseases in humans caused by RAGE. Such diseases or disease states include acute and chronic inflammation, the development of diabetic late complications such as increased vascular permeability, nephropathy, atherosclerosis, and retinopathy, the development of Alzheimer's disease, erectile dysfunction, and tumor invasion and metastasis.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the present invention provides certain substituted azole compounds. Such compounds are useful in the modulation, preferably in the inhibition, of the interaction of RAGE with its physiological ligands, as will be discussed in more detail below.

In a second aspect, the present invention provides compounds of Formula (I):

wherein R₁ comprises -hydrogen, -aryl, -heteroaryl, -cycloalkyl, -heterocyclyl, -alkyl, -alkenyl, -alkynyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-heterocyclyl, -alkylene-cycloalkyl, -fused cycloalkylaryl, -fused cycloalkylheteroaryl, -fused heterocyclylaryl, -fused heterocyclylheteroaryl, -alkylene-fused cycloalkylaryl, -alkylene-fused cycloalkylheteroaryl, -alkylene-fused heterocyclylaryl, -alkylene-fused heterocyclylheteroaryl, or -G₁-G₂-G₃-R₅

-   wherein     -   G₁ and G₃ independently comprise alkylene, alkenylene,         alkynylene, cycloalkylene, heterocyclylene, arylene,         heteroarylene, (aryl)alkylene, (heteroaryl) alkylene,         (aryl)alkenylene, (heteroaryl)alkenylene, or a direct bond;     -   G₂ comprises —O—, —S—, —S(O)—, —N(R₆)—, —S(O)₂—, —C(O)—,         —O—C(O)—, —C(O)—O—, —C(O)N(R₆)—, —N(R₆)C(O)—, —S(O₂)N(R₆)—,         N(R₆)S(O₂)—, —O-alkylene-C(O)—, —(O)C-alkylene-O—, —O-alkylene-,         -alkylene-O—, alkylene, alkenylene, alkynylene, cycloalkylene,         heterocyclylene, arylene, heteroarylene, fused         cycloalkylarylene, fused cycloalkylheteroarylene, fused         heterocyclylarylene, fused heterocyclylheteroarylene, or a         direct bond, wherein R₆ comprises hydrogen, aryl, alkyl,         -alkylene-aryl, alkoxy, or -alkylene-O-aryl; and     -   R₅ comprises hydrogen, aryl, heteroaryl, cycloalkyl,         heterocyclyl, alkyl, alkenyl, alkynyl, -alkylene-aryl,         -alkylene-heteroaryl, -alkylene-heterocyclyl,         -alkylene-cycloalkyl, fused cycloalkylaryl, fused         cycloalkylheteroaryl, fused heterocyclylaryl, fused         heterocyclylheteroaryl, -alkylene-fused cycloalkylaryl,         -alkylene-fused cycloalkylheteroaryl, -alkylene-fused         heterocyclylaryl, or -alkylene-fused heterocyclylheteroaryl;         A₁ comprises O, S, or —N(R₂)—; -   wherein     -   R₂ comprises         -   a) —H;         -   b) -aryl;         -   c) -heteroaryl;         -   d) -cycloalkyl         -   e) heterocyclyl;         -   f) -alkyl;         -   g) -alkenyl;         -   h) -alkynyl;         -   i)-alkylene-aryl,         -   j) -alkylene-heteroaryl,         -   k) -alkylene-heterocyclyl,         -   l) -alkylene-cycloalkyl;         -   m) -fused cycloalkylaryl,         -   n) -fused cycloalkylheteroaryl,         -   o) -fused heterocyclylaryl,         -   p) -fused heterocyclylheteroaryl;         -   q) -alkylene-fused cycloalkylaryl,         -   r) -alkylene-fused cycloalkylheteroaryl,         -   s)-alkylene-fused heterocyclylaryl,         -   t) -alkylene-fused heterocyclylheteroaryl; or         -   u) a group of the formula

-   -   -   -   wherein                 -   A₃ comprises an aryl or heteroaryl group;                 -   L₁ and L₂ independently comprise alkylene or                     alkenylene; and                 -   L₃ comprises a direct bond, alkylene, —O—, —S—,                     —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—,                     —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

-   -   -   -   -    wherein R₃₀, R₃₁, and R₃₂ independently comprise                     hydrogen, aryl, heteroaryl, alkyl, alkylene-aryl, or                     -alkylene-heteroaryl;                     R₃ and R₄ independently comprise

-   a) -hydrogen,

-   b) -halogen,

-   c) -hydroxyl,

-   d) -cyano,

-   e) -carbamoyl,

-   f) -carboxyl,

-   g) -aryl,

-   h) -heteroaryl,

-   i) -cycloalkyl,

-   j) -heterocyclyl,

-   k) -alkyl,

-   l) -alkenyl,

-   m) -alkynyl,

-   n) -alkylene-aryl,

-   o) -alkylene-heteroaryl,

-   p) -alkylene-heterocyclyl,

-   q) -alkylene-cycloalkyl,

-   r) -fused cycloalkylaryl,

-   s) -fused cycloalkylheteroaryl,

-   t) -fused heterocyclylaryl,

-   u) -fused heterocyclylheteroaryl,

-   v) -alkylene-fused cycloalkylaryl,

-   w) -alkylene-fused cycloalkylheteroaryl,

-   x) -alkylene-fused heterocyclylaryl,

-   y) -alkylene-fused heterocyclylheteroaryl;

-   z) —C(O)—O-alkyl;

-   aa) —C(O)—O-alkylene-aryl;

-   bb) —C(O)—NH-alkyl;

-   cc) —C(O)—NH-alkylene-aryl;

-   dd) —SO₂-alkyl;

-   ee) —SO₂-alkylene-aryl;

-   ff) —SO₂-aryl;

-   gg) —SO₂—NH-alkyl;

-   hh) —SO₂—NH— alkylene-aryl;

-   ii) —C(O)-alkyl;

-   jj) —C(O)-alkylene-aryl;

-   kk) -G₄-G₅-G₆-R₇;

-   ll) —Y₁-alkyl;

-   mm) —Y₁-aryl;

-   nn) —Y₁-heteroaryl;

-   oo) —Y₁-alkylene-aryl;

-   pp) —Y₁-alkylene-heteroaryl;

-   qq) —Y₁-alkylene-NR₉R₁₀; or

-   rr) —Y₁-alkylene-W₁—R₁₁;     -   wherein         -   G₄ and G₆ independently comprise alkylene, alkenylene,             alkynylene, cycloalkylene, heterocyclylene, arylene,             heteroarylene, (aryl)alkylene, (heteroaryl)alkylene,             (aryl)alkenylene, (heteroaryl)alkenylene, or a direct bond;         -   G₅ comprises —O—, —S—, —N(R₈)—, —S(O)—, —S(O)₂—, —C(O)—,             —O—C(O)—, —C(O)—O—, —C(O)N(R₈)—, N(R₈)C(O)—, —S(O₂)N(R₈)—,             N(R₈)S(O₂)—, —O-alkylene-C(O)—, —(O)C-alkylene-O—,             —O-alkylene-, -alkylene-O—, alkylene, alkenylene,             alkynylene, cycloalkylene, heterocyclylene, arylene,             heteroarylene, fused cycloalkylarylene, fused             cycloalkylheteroarylene, fused heterocyclylarylene, fused             heterocyclylheteroarylene, or a direct bond, wherein R₈             comprises -hydrogen, -aryl, -alkyl, -alkylene-aryl, or             -alkylene-O-aryl;         -   R₇ comprises hydrogen, aryl, heteroaryl, cycloalkyl,             heterocyclyl, alkyl, alkenyl, alkynyl, alkylene-aryl,             -alkylene-heteroaryl, -alkylene-heterocyclyl,             -alkylene-cycloalkyl, fused cycloalkylaryl, fused             cycloalkylheteroaryl, fused heterocyclylaryl, fused             heterocyclylheteroaryl, alkylene-fused cycloalkylaryl,             -alkylene-fused cycloalkylheteroaryl, -alkylene-fused             heterocyclylaryl, or -alkylene-fused heterocyclylheteroaryl;         -   Y₁ and W₁ independently comprise —CH₂—, —O—, —N(H), —S—,             SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—,             —C(O)—O—, —NHSO₂NH—, —O—CO—,

-   -   -   -   wherein R₁₂ and R₁₃ independently comprise aryl, alkyl,                 -alkylene-aryl, alkoxy, or -alkylene-O-aryl; and

        -   R₉, R₁₀, and R₁₁ independently comprise aryl, heteroaryl,             alkyl, -alkylene-heteroaryl, or -alkylene-aryl; and R₉ and             R₁₀ may be taken together to form a ring having the formula             —(CH₂)_(o)—X₁—(CH₂)_(p)— bonded to the nitrogen atom to             which R₉ and R₁₀ are attached,             -   wherein                 -   o and p are, independently, 1, 2, 3, or 4; and                 -   X₁ comprises a direct bond, —CH₂—, —O—, —S—,                     —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—,                     —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

-   -   -   -   wherein R₁₄ and R₁₅ independently hydrogen, aryl,                 heteroaryl, alkyl, -alkylene-aryl, or                 -alkylene-heteroaryl;                 wherein

-   the aryl and/or alkyl group(s) in R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈,     R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, and R₁₅ may be optionally substituted     1-4 times with a substituent group, wherein said substituent     group(s) or the term substituted refers to a group comprising:     -   a) —H,     -   b) -halogen,     -   c) -hydroxyl,     -   d)-cyano,     -   e) -carbamoyl,     -   f) -carboxyl,     -   g) —Y₂-alkyl;     -   h) —Y₂-aryl;     -   i) —Y₂-heteroaryl;     -   j) —Y₂-alkylene-heteroarylaryl;     -   k) —Y₂-alkylene-aryl;     -   l) —Y₂-alkylene-W₂—R₁₈;     -   m) —Y₃—Y₄—NR₂₃R₂₄,     -   n) —Y₃—Y₄—NH—C(═NR₂₅)NR₂₃R₂₄,     -   o) —Y₃—Y₄—C(═NR₂₅)NR₂₃R₂₄, or     -   p) —Y₃—Y₄—Y₅-A₂,         -   wherein             -   Y₂ and W₂ independently comprise —CH₂—, —O—, —N(H), —S—,                 SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—,                 —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—S(O)₂—, —O—CO—,

-   -   -   -   -   wherein;                 -    R₁₉ and R₂₀ independently comprise hydrogen, aryl,                     alkyl, -alkylene-aryl, alkoxy, or -alkylene-O-aryl;                     and

            -   R₁₈ comprises aryl, alkyl, -alkylene-aryl,                 -alkylene-heteroaryl, and -alkylene-O-aryl;

            -   Y₃ and Y₅ independently comprise a direct bond, —CH₂—,                 —O—, —N(H), —S—, SO₂—, —C(O)—, —CON(H)—, —NHC(O)—,                 —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—,                 —O—CO—,

-   -   -   -   -   wherein R₂₇ and R₂₆ independently comprise aryl,                     alkyl, -alkylene-aryl, alkoxy, or -alkyl-O-aryl;

            -   Y₄ comprises                 -   a) -alkylene;                 -   b) -alkenylene;                 -   c) -alkynylene;                 -   d) -arylene;                 -   e) -heteroarylene;                 -   f) -cycloalkylene;                 -   g) -heterocyclylene;                 -   h) -alkylene-arylene;                 -   i) -alkylene-heteroarylene;                 -   j) -alkylene-cycloalkylene;                 -   k) -alkylene-heterocyclylene;                 -   l) -arylene-alkylene;                 -   m) -heteroarylene-alkylene;                 -   n) -cycloalkylene-alkylene;                 -   o) -heterocyclylene-alkylene;                 -   p) —O—;                 -   q) —S—;                 -   r) —S(O₂)—; or                 -   s) —S(O)—;                 -    wherein said alkylene groups may optionally contain                     one or more O, S, S(O), or SO₂ atoms;

            -   A₂ comprises                 -   a) heterocyclyl, fused arylheterocyclyl, or fused                     heteroarylheterocyclyl, containing at least one                     basic nitrogen atom,                 -   b) -imidazolyl, or                 -   c) -pyridyl; and

            -   R₂₃, R₂₄, and R₂₅ independently comprise hydrogen, aryl,                 heteroaryl, -alkylene-heteroaryl, alkyl, -alkylene-aryl,                 -alkylene-O-aryl, or -alkylene-O-heteroaryl; and R₂₃ and                 R₂₄ may be taken together to form a ring having the                 formula —(CH₂)_(s)—X₃—(CH₂)_(t)— bonded to the nitrogen                 atom to which R₂₃ and R₂₄ are attached                 -   wherein                 -    s and t are, independently, 1, 2, 3, or 4;                 -    X₃ comprises a direct bond, —CH₂—, —O—, —S—,                     —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—,                     —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

-   -   -   -   -    wherein R₂₈ and R₂₉ independently comprise                     hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl,                     or -alkylene-heteroaryl;                     wherein

-   either     -   at least one of the groups R₁, R₂, R₃ and R₄ are substituted         with at least one group of the formula —Y₃—Y₄—NR₂₃R₂₄,         —Y₃—Y₄—NH—C(═NR₂₅)NR₂₃R₂₄, —C(═NR₂₅)NR₂₃R₂₄, or —Y₃—Y₄—Y₅-A₂,         with the proviso that no more than one of R₂₃, R₂₄, and R₂₅ may         comprise aryl or heteroaryl;

-   or     -   R₂ is a group of the formula

wherein

-   one of R₃ and R₄, R₃ and R₂, or R₁ and R₂ may be taken together to     constitute, together with the atoms to which they are bonded, an     aryl, heteroaryl, fused arylcycloalkyl, fused arylheterocyclyl,     fused heteroarylcycloalkyl, or fused heteroarylheterocyclyl ring     system, -   wherein     -   said ring system or R₁, R₂, R₃, or R₄ is substituted with at         least one group of the formula         -   a) —Y₅—Y₆—NR₃₃R₃₄;         -   b) —Y₅—Y₆—NH—C(═NR₃₅)NR₃₃R₃₄;         -   c) —Y₅—Y₆—C(═NR₃₅)NR₃₃R₃₄; or         -   d) —Y₅—Y₆—Y₇-A₄;         -   wherein             -   Y₅ and Y₇ independently comprise a direct bond, —CH₂—,                 —O—, —N(H), —S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—,                 —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—CO—,

-   -   -   -   -   wherein R₃₆ and R₃₇ independently comprise aryl,                     alkyl, -alkylene-aryl, alkoxy, or -alkyl-O-aryl;

            -   Y₆ comprises                 -   a) alkylene;                 -   b) alkenylene;                 -   c) alkynylene;                 -   d) arylene;                 -   e) heteroarylene;                 -   f) cycloalkylene;                 -   g) heterocyclylene;                 -   h) alkylene-arylene;                 -   i) alkylene-heteroarylene;                 -   j) alkylene-cycloalkylene;                 -   k) alkylene-heterocyclylene;                 -   l) arylene-alkylene;                 -   m) heteroarylene-alkylene;                 -   n) cycloalkylene-alkylene;                 -   o) heterocyclylene-alkylene;                 -   p) —O—;                 -   q) —S—;                 -   r) —S(O₂)—; or                 -   s) —S(O)—;                 -   wherein said alkylene groups may optionally contain                     one or more O, S, S(O), or SO₂ atoms;

            -   A₄ comprises                 -   a) heterocyclyl, fused arylheterocyclyl, or fused                     heteroarylheterocyclyl, containing at least one                     basic nitrogen atom,                 -   b) -imidazolyl, or                 -   c) -pyridyl; and

            -   R₃₃, R₃₄ and R₃₅ independently comprise hydrogen, aryl,                 heteroaryl, alkyl, -alkylene-aryl, or -alkylene-O-aryl;                 with the proviso that no two of R₃₃, R₃₄ and R₃₅ are                 aryl and/or heteroaryl; and R₃₃ and R₃₄ may be taken                 together to form a ring having the formula                 —(CH₂)_(u)—X₄—(CH₂)_(v)— bonded to the nitrogen atom to                 which R₃₃ and R₃₄ are attached,                 -   wherein                 -    u and v are, independently, 1, 2, 3, or 4;                 -    X₄ comprises a direct bond, —CH₂—, —O—, —S—,                     —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—,                     —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

-   -   -   -   -    wherein R₃₆ and R₃₇ independently comprise                     hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl,                     or -alkylene-heteroaryl; and

    -   wherein said ring system is optionally substituted with         substituents comprising         -   a) —H;         -   b) -halogen;         -   c) -hydroxyl;         -   d) -cyano;         -   e) -carbamoyl;         -   f) -carboxyl;         -   g) —Y₈-alkyl;         -   h) —Y₈-aryl;         -   i) —Y₈-heteroaryl;         -   j) —Y₈-alkylene-aryl;         -   k) —Y₈-alkylene-heteroaryl;         -   l) —Y₈-alkylene-NR₃₈R₃₉; or         -   m) —Y₈-alkylene-W₃—R₄₀;             -   wherein                 -   Y₈ and W₃ independently comprise —CH₂—, —O—, —N(H),                     —S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—,                     —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—CO—,

-   -   -   -   -    wherein R₄₁ and R₄₂ independently comprise aryl,                     alkyl, -alkylene-aryl, alkoxy, or -alkyl-O-aryl; and                 -   R₃₈, R₃₉, and R₄₀ independently comprise hydrogen,                     aryl, alkyl, -alkylene-aryl, -alkylene-heteroaryl,                     and -alkyene-O-aryl; and R₃₈ and R₃₉ may be taken                     together to form a ring having the formula                     —(CH₂)_(w)—X₇—(CH₂)_(x)— bonded to the nitrogen atom                     to which R₃₈ and R₃₉ are attached wherein                 -    w and x are, independently, 1, 2, 3, or 4;                 -    X₇ comprises a direct bond, —CH₂—, —O—, —S—,                     —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—,                     —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

-   -   -   -   -    wherein R₄₃ and R₄₄ independently comprise                     hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl,                     or -alkylene-heteroaryl;                     or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the compound of Formula (I) comprises a compound of the Formula (Ia

wherein R₁ comprises -hydrogen, -aryl, -heteroaryl, -cycloalkyl, -heterocyclyl, -alkyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-heterocyclyl, -alkylene-cycloalkyl, or -G₁-G₂-G₃-R₅

-   wherein     -   G₁ and G₃ independently comprise alkylene or a direct bond;     -   G₂ comprises —O—, —CO₂—, or a direct bond; and     -   R₅ comprises hydrogen, aryl, heteroaryl, cycloalkyl,         heterocyclyl, alkyl, alkenyl, alkynyl, -alkylene-aryl,         -alkylene-heteroaryl, -alkylene-heterocyclyl, or         -alkylene-cycloalkyl.         R₂ comprises -   a) -hydrogen, -   b) -aryl, -   c) -heteroaryl, -   d) -heterocyclyl, -   e) -alkyl, -   f) -alkylene-aryl, -   g) -alkylene-heteroaryl, -   h) -alkylene-heterocyclyl, -   i) -fused cycloalkylaryl, -   j) -fused cycloalkylheteroaryl, -   k) -fused heterocyclylaryl, -   l) -fused heterocyclylheteroaryl; -   m) -alkylene-fused cycloalkylaryl, -   n) -alkylene-fused cycloalkylheteroaryl, -   o) -alkylene-fused heterocyclylaryl, -   p) -alkylene-fused heterocyclylheteroaryl; or -   q) a group of the formula

-   -   wherein         -   A₃ comprises an aryl or heteroaryl group;         -   L₁ and L₂ independently comprise alkylene or alkenylene;         -   L₃ comprises a direct bond, alkylene, —O—, —S—, —S(O₂)—,             —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—,             —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

-   -   -   -   wherein R₃₀, R₃₁, and R₃₂ independently comprise                 hydrogen, aryl, heteroaryl, alkyl, alkylene-aryl, or                 -alkylene-heteroaryl;                 R₃ and R₄ independently comprise

-   a) -hydrogen;

-   b) -halogen,

-   c) -hydroxyl,

-   d) -cyano,

-   e) -carbamoyl,

-   f) -carboxyl;

-   g) -aryl,

-   h) -heteroaryl,

-   i) -cycloalkyl,

-   j) -heterocyclyl,

-   k) -alkyl,

-   l)-alkenyl,

-   m)-alkynyl,

-   n)-alkylene-aryl,

-   o) -alkylene-heteroaryl,

-   p) -alkylene-heterocyclyl,

-   q) -alkylene-cycloalkyl,

-   r) -fused cycloalkylaryl,

-   s) -fused cycloalkylheteroaryl,

-   t) -fused heterocyclylaryl,

-   u) -fused heterocyclylheteroaryl,

-   v) -alkylene-fused cycloalkylaryl,

-   w) -alkylene-fused cycloalkylheteroaryl,

-   x) -alkylene-fused heterocyclylaryl,

-   y) -alkylene-fused heterocyclylheteroaryl;

-   z) —C(O)—O-alkyl;

-   aa) —C(O)—O-alkylene-aryl;

-   bb) —C(O)—NH-alkyl;

-   cc) —C(O)—NH-alkylene-aryl;

-   dd) —SO₂-alkyl;

-   ee) —SO₂-alkylene-aryl;

-   ff) —SO₂-aryl;

-   gg) —SO₂—NH-alkyl;

-   hh) —SO₂—NH— alkylene-aryl

-   ii) —C(O)-alkyl;

-   jj) —C(O)-alkylene-aryl;

-   kk) -G₄-G₅-G₆-R₇

-   ll) —Y₁-alkyl;

-   mm) —Y₁-aryl;

-   nn) —Y₁-heteroaryl;

-   oo) —Y₁-alkylene-aryl;

-   pp) —Y₁-alkylene-heteroaryl;

-   qq) —Y₁-alkylene-NR₉R₁₀; and

-   rr) —Y₁-alkylene-W₁—R₁₁;     -   wherein         -   G₄ and G₆ independently comprise alkylene, alkenylene,             alkynylene, cycloalkylene, heterocyclylene, arylene,             heteroarylene, (arylalkylene, (heteroary) alkylene,             (aryl)alkenylene, (heteroaryl)alkenylene, or a direct bond;         -   G₅ comprises —O—, —S—, —N(R₈)—, —S(O)—, —S(O)₂—, —C(O)—,             —C(O)N(R₈)—, N(R₈)C(O)—, —S(O₂)N(R₈)—, N(R₈)S(O₂)—,             —O-alkylene-C(O)—, —(O)C-alkylene-O—, —O-alkylene-,             -alkylene-O—, alkylene, alkenylene, alkynylene,             cycloalkylene, heterocyclylene, arylene, heteroarylene,             fused cycloalkylaryl, fused cycloalkylheteroaryl, fused             heterocyclylaryl, fused heterocyclylheteroaryl, or a direct             bond, wherein R₈ comprises -hydrogen, -aryl, -alkyl,             -alkylene-aryl, or -alkylene-O-aryl;         -   R₇ comprises hydrogen; aryl, heteroaryl, cycloalkyl,             heterocyclyl, alkyl, alkenyl, alkynyl, alkylene-aryl,             -alkylene-heteroaryl, -alkylene-heterocyclyl,             -alkylene-cycloalkyl, fused cycloalkylaryl, fused             cycloalkylheteroaryl, fused heterocyclylaryl, fused             heterocyclylheteroaryl, alkylene-fused cycloalkylaryl,             -alkylene-fused cycloalkylheteroaryl, -alkylene-fused             heterocyclylaryl, or -alkylene-fused heterocyclylheteroaryl;         -   Y₁ and W₁ independently comprise —CH₂—, —O—, —N(H), —S—,             SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—,             —C(O)—O—, —NHSO₂NH—, —O—CO—,

-   -   -   -   wherein R₁₂ and R₁₃ independently comprise aryl, alkyl,                 -alkylene-aryl, alkoxy, or -alkylene-O-aryl;

        -   R₉, R₁₀, and R₁₁ independently comprise aryl, heteroaryl,             alkyl, -alkylene-heteroaryl, or -alkylene-aryl; and R₉ and             R₁₀ may be taken together to form a ring having the formula             —(CH₂)_(o)—X₁—(CH₂)_(p)— bonded to the nitrogen atom to             which R₉ and R₁₀ are attached,             -   wherein                 -   o and p are, independently, 1, 2, 3, or 4;                 -   X₁ comprises a direct bond, —CH₂—, —O—, —S(O₂)—,                     —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—,                     —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

-   -   with the proviso that R₃ and R₄ can not both be hydrogen.

In one group of preferred embodiments of Formula (Ia), R₁ comprises a hydrogen, methyl, ethyl, propyl, butyl, iso-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-butenyl, tert-butyl, 3-cyclohexyl-propyl, 3-phenoxy-propyl, methoxymethyl, 4-fluoro-phenyl, 3-(4-chlorophenoxy)-propyl, 2,4,4-trimethyl-pentyl, 1-ethyl-propyl, 1-propyl-butyl, benzyloxymethyl, 2-cyclopropy-ethyl, 2-phenyl-ethyl, 4-tert-butylphenoxymethyl, 4-tert-butylcyclohexyl, 4-butylcyclohexyl, 4-ethylcyclohexyl, 3-methoxycarbonyl -1-propyl, or 2-(pyridin-3-yl)-ethyl group.

In another group of preferred embodiments of Formula (Ia), R₂ comprises a phenyl or 1,2,3,4-tetrahydroisoquinoline group, wherein the phenyl group is substituted with at least one substitutent comprising

-   -   a) —Y₂-alkyl;     -   b) —Y₂-aryl;     -   c) —Y₂-heteroaryl;     -   d) —Y₂-alkylene-heteroarylaryl;     -   e) —Y₂-alkylene-aryl;     -   f) —Y₂-alkylene-W₂—R₁₈;     -   g) —Y₃—Y₄—NR₂₃R₂₄;     -   h) —Y₃—Y₄—NH—C(═NR₂₅)NR₂₃R₂₄;     -   i) —Y₃—Y₄—C(═NR₂₅)NR₂₃R₂₄; or     -   j) —Y₃—Y₄—Y₅-A₂;         -   wherein             -   Y₂ and W₂ independently comprise —CH₂— or —O—, and             -   R₁₈ comprises aryl, alkyl, -alkylene-aryl,                 -alkylene-heteroaryl, or -alkylene-O-aryl;             -   Y₃ and Y₅ independently comprise a direct bond, —CH₂—,                 —O—, —N(H), —S—, SO₂—, —C(O)—, —CON(H)—, —NHC(O)—,                 —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—,                 —O—CO—,

-   -   -   -   -   wherein R₂₇ and R₂₆ independently comprise aryl,                     alkyl, -alkylene-aryl, alkoxy, or -alkyl-O-aryl;

            -   Y₄ comprises                 -   a) -alkylene;                 -   b) -alkenylene;                 -   c) -alkynylene;                 -   d) -arylene;                 -   e) -heteroarylene;                 -   f) -cycloalkylene;                 -   g) -heterocyclylene;                 -   h) -alkylene-arylene;                 -   i) -alkylene-heteroarylene;                 -   j) -alkylene-cycloalkylene;                 -   k) -alkylene-heterocyclylene;                 -   l) -arylene-alkylene;                 -   m) -heteroarylene-alkylene;                 -   n) -cycloalkylene-alkylene;                 -   t) -heterocyclylene-alkylene;                 -   u) —O—;                 -   v) —S—;                 -   w) —S(O₂)—; or                 -   x) —S(O)—;                 -    wherein said alkylene groups may optionally contain                     one or more O, S, S(O), or SO₂ atoms;

            -   A₂ comprises                 -   a) heterocyclyl, fused arylheterocyclyl, or fused                     heteroarylheterocyclyl, containing at least one                     basic nitrogen atom,                 -   b) -imidazolyl, or                 -   c) -pyridyl; and

            -   R₂₃, R₂₄, and R₂₅ independently comprise hydrogen, aryl,                 heteroaryl, -alkylene-heteroaryl, alkyl, -alkylene-aryl,                 -alkylene-O-aryl, or -alkylene-O-heteroaryl; and R₂₃ and                 R₂₄ may be taken together to form a ring having the                 formula —(CH₂)_(s)—X₃—(CH₂)_(t)— bonded to the nitrogen                 atom to which R₂₃ and R₂₄ are attached                 -   wherein                 -    s and t are, independently, 1, 2, 3, or 4;                 -    X₃ comprises direct bond, —CH₂—, —O—, —S—, —S(O₂)—,                     —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—,                     —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

-   -   -   -   -    wherein R₂₈ and R₂₉ independently comprise                     hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl,                     or -alkylene-heteroaryl.

In another group of preferred embodiments of compounds of Formula (Ia), R₂ comprises 4-[3-(N,N′-diethylamino)-propoxy]-phenyl, 4-[3-(N,N′-dimethylamino)-propoxy]-phenyl, 3-[3-(N,N′-diethylamino)-propoxy]-phenyl, 4-(3-fluoro-4-trifluoromethyl-phenoxy)-phenyl, 4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl, 4-(4-trifluoromethoxy-phenoxy)-phenyl, 4-(3,4-dichloro-phenoxy)-phenyl, 4-(3,5-bis-trifluoromethyl-phenoxy)-phenyl, 4-benzyloxy-phenyl, 4-(4-methyloxy-phenoxy)-phenyl, 4-(2-hexyl-4-chloro-phenoxy)-phenyl, 4-(4-phenyl-phenoxy)-phenyl, 4-(4-acetamido-phenoxy)-phenyl, 4-(4-methyl-phenoxy)-phenyl, 4-(4-fluoro-phenoxy)-phenyl, 4-(4-bromo-phenoxy)-phenyl, 4-(4-chloro-phenoxy)-phenyl, 4-(4-amino-phenoxy)-phenyl, 4-(3-ethyl-4-chloro-phenoxy)-phenyl, 4-[2-(N-ethylamino)-ethoxy]-phenyl, 4-[2,2′-dimethyl-3-(N,N′-dimethylamino)-propoxy]-phenyl, 1,2,3,4-tetrahydroisoquinolin-7-yl, 4-(4-benzamido-phenoxy)-phenyl, 4-(4-isonicotinamido-phenoxy)-phenyl, 4-[2-(N-methyl-N′-pyrid-4-yl)-ethoxy]-phenyl, 4-[3-(diethylmethyl ammonium)-propoxy)]-phenyl, 4-(2,5-di-fluoro-benzyloxy)-phenyl, 4-(2,4-dichloro-phenoxy)-phenyl, 4-(naphthalen-2-yloxy)-phenyl, 4-(6-methoxy-naphthalen-2-yloxy)-phenyl, 4-(4-methoxy-naphthalen-2-yloxy)-phenyl, 4-(6-hydroxy-naphthalen-2-yloxy)-phenyl, 4-(dibenzofuran-2-yloxy)-phenyl, 4-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl, 4-[2-(piperazin-1-yl)-ethoxy]-phenyl, or 4-(4-tert-butyl-phenoxy)-phenyl.

In another group of preferred embodiments of Formula (Ia), R₃ comprises hydrogen; and R₄ comprises a phenyl group, wherein the phenyl group is substituted with at least one substituent comprising

-   -   a) —Y₂-alkyl;     -   b) —Y₂-aryl;     -   c) —Y₂-heteroaryl;     -   d) —Y₂-alkylene-heteroarylaryl;     -   e) —Y₂-alkylene-aryl;     -   f) —Y₂-alkylene-W₂—R₁₈;     -   g) —Y₃—Y₄—NR₂₃R₂₄;     -   h) —Y₃—Y₄—NH—C(═NR₂₅)NR₂₃R₂₄;     -   i) —Y₃—Y₄—C(═NR₂₅)NR₂₃R₂₄; or     -   j) —Y₃—Y₄—Y₅-A₂;         -   wherein             -   Y₂ and W₂ independently comprise —CH₂— or —O—;             -   R₁₈ comprises aryl, alkyl, -alkylene-aryl,                 -alkylene-heteroaryl, or -alkylene-O-aryl;             -   Y₃ and Y₅ independently comprise a direct bond, —CH₂—,                 —O—, —N(H), —S—, SO₂—, —C(O)—, —CON(H)—, —NHC(O)—,                 —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—,                 —O—CO—,

-   -   -   -   -   wherein R₂₇ and R₂₆ independently comprise aryl,                     alkyl, -alkylene-aryl, alkoxy, or -alkyl-O-aryl;

            -   Y₄ comprises                 -   a) -alkylene;                 -   b) -alkenylene;                 -   c) -alkynylene;                 -   d) -arylene;                 -   e) -heteroarylene;                 -   f) -cycloalkylene;                 -   g) -heterocyclylene;                 -   h) -alkylene-arylene;                 -   i) -alkylene-heteroarylene;                 -   j) -alkylene-cycloalkylene;                 -   k) -alkylene-heterocyclylene;                 -   l) -arylene-alkylene;                 -   m) -heteroarylene-alkylene;                 -   n) -cycloalkylene-alkylene;                 -   o) -heterocyclylene-alkylene;                 -   p) —O—;                 -   q) —S—;                 -   r) —S(O₂)—; or                 -   s) —S(O)—;                 -    wherein said alkylene groups may optionally contain                     one or more O, S, S(O), or SO₂ atoms;

            -   A₂ comprises                 -   a) heterocyclyl, fused arylheterocyclyl, or fused                     heteroarylheterocyclyl, containing at least one                     basic nitrogen atom,                 -   b) -imidazolyl, or                 -   c) -pyridyl;

            -   R₂₃, R₂₄, and R₂₅ independently comprise hydrogen, aryl,                 heteroaryl, -alkylene-heteroaryl, alkyl, -alkylene-aryl,                 -alkylene-O-aryl, or -alkylene-O-heteroaryl; and R₂₃ and                 R₂₄ may be taken together to form a ring having the                 formula —(CH₂)_(s)—X₃—(CH₂)_(t)— bonded to the nitrogen                 atom to which R₂₃ and R₂₄ are attached                 -   wherein                 -    s and t are, independently, 1, 2, 3, or 4;                 -    X₃ comprises direct bond, —CH₂—, —O—, —S—, —S(O₂)—,                     —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—,                     —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

-   -   -   -   -    wherein R₂₈ and R₂₉ independently comprise                     hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl,                     or -alkylene-heteroaryl.

In a more preferred group of compounds of Formula (Ia), R₃ comprises hydrogen and R₄ comprises 4-{2-[(4-chlorophenyl)-ethoxy]}-phenyl, 4-[3-(N,N′-diethylamino)-propoxy]-phenyl, 4-(2-amino-ethoxy)-phenyl, 4-[2-(N-methyl-N′-pyridin-4-yl-amino)-ethoxy]-phenyl, 4-[2-(N-ethyl-N′-pyridin-4-yl-amino)-ethoxy]-phenyl, 4-[2-(N-pyridin-4-yl-amino)-ethoxy]-phenyl, 4-(4-amino-pyridin-3-yl-oxy)-phenyl, 4-[(pyridin-4-yl)-amino]-phenyl, 4-[2-(N,N′-bis-pyridin-2-ylmethyl-amino)-ethoxy]-phenyl, 4-[2-(guanidinyl)-ethoxy]-phenyl, 4-{2-[4-(pyridin-4-yl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl, 4-[2-(N-methyl-N′-3-methylpyridin-4-yl-amino)-ethoxy]-phenyl, 4-(4-hydroxy-pyrrolidin-2-ylmethyloxy)-phenyl, 4-(4-amino-3,5-dimethyl-pyrrolidin-2-ylmethyloxy)-phenyl, dibenzofuran-2-yl, 4-[3-(piperazin-1-yl)-propoxy]-phenyl, 4-(piperazin-4-yloxy)-phenyl, 4-[5-(piperazin-1-yl)-pentoxy]-phenyl, 4-[3-(N,N′-dimethylamino)-propoxy]-phenyl, 4-(3-fluoro-4-trifluoromethyl-phenoxy)-phenyl, 4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl, 4-(4-phenyl-phenoxy)-phenyl, 4-(3-trifluoromethoxy-phenoxy)-phenyl, 4-(4-trifluoromethyl-benzyloxy)-phenyl, 4-(3,4-dichloro-phenoxy)-phenyl, 4-(2,4-dichloro-phenoxy)-phenyl, 4-(1-ethyl-piperidin-3-yloxy)-phenyl, 4-benzyloxy-phenyl, 4-[(1-ethyl-piperidin-3-yl)-methoxy]-phenyl, 4-(4-phenoxy-benzyloxy)-phenyl, 4-(4-benzyloxy-benzyloxy)-phenyl, 4-(2-benzenesulfonylmethyl-benzyloxy)-phenyl, 4-(3,4,5-trimethoxybenzyloxy)-phenyl, 4-[2-(pyrrolidin-1-yl)-ethoxy]-phenyl, 4-[2-(piperidin-1-yl)-ethoxy]-phenyl, 4-[2,2′-dimethyl-3-(N,N′-dimethylamino)-propoxy]-phenyl, 4-[2-(N,N′-diisopropylamino)-ethoxy]-phenyl, 4-(adamantan-1-ylmethoxy)-phenyl, 3-[(2,6-dichlorophenyl)-4-methyl-isoxazol-5-ylmethyloxy]-phenyl, 4-(4-bromo-benzyloxy)-phenyl, 4-(4-chlorophenoxy)-phenyl, 4-[4-{(1-ethyl-piperidin-4-yl)-methylamino}-phenoxy]-phenyl, 4-(3,3-diphenylpropoxy)-phenyl, 4-[3,3-Bis-(4-fluorophenyl)-propoxy]-phenyl, 4-[3,3-Bis-(4-chlorophenyl)-allyoxy]-phenyl, 4-(4-chlorophenoxy)-naphthalenyl, 4-[2-(biphenyl-4-yl)-acetamido]-phenyl, 4-(2-(9H-carbazole)-ethoxy]-phenyl, 4-[4-methoxyphenyoxy]-phenyl, 4-(4-tert-butyl-phenoxy)-phenyl, or 4-(naphthylen-2-ylmethoxy)-phenyl.

In another preferred embodiment, the compound Formula (I) comprises the compound of Formula (Ib),

wherein

-   R₁ comprises -hydrogen, -aryl, -heteroaryl, -cycloalkyl,     -heterocyclyl, -alkyl, -alkenyl, -alkylene-aryl,     -alkylene-heteroaryl, -alkylene-heterocyclyl, -alkylene-cycloalkyl,     -fused cycloalkylaryl, -fused cycloalkylheteroaryl, -fused     heterocyclylaryl, -fused heterocyclylheteroaryl, -alkylene-fused     cycloalkylaryl, -alkylene-fused cycloalkylheteroaryl,     -alkylene-fused heterocyclylaryl, -alkylene-fused     heterocyclylheteroaryl, or -G₁-G₂-G₃-R₅     -   wherein         -   G₁ and G₃ independently comprise alkylene, alkenylene,             alkynylene, cycloalkylene, heterocyclylene, arylene,             heteroarylene, (aryl)alkylene, (heteroaryl) alkylene,             (aryl)alkenylene, (heteroaryl)alkenylene, or a direct bond;         -   G₂ comprises —O—, —S—, —S(O)—, —N(R₆)—, —S(O)₂—, —C(O)—,             —CO₂—, —C(O)N(R₆)—, N(R₆)C(O)—, —S(O₂)N(R₆)—, N(R₆)S(O₂)—,             —O-alkylene-C(O)—, —(O)C-alkylene-O—, —O-alkylene-,             -alkylene-O—, alkylene, alkenylene, alkynylene,             cycloalkylene, heterocyclylene, arylene, heteroarylene,             fused cycloalkylaryl, fused cycloalkylheteroaryl, fused             heterocyclylaryl, fused heterocyclylheteroaryl, or a direct             bond, wherein R₆ comprises hydrogen, aryl, alkyl,             -alkylene-aryl, alkoxy, or -alkylene-O-aryl; and         -   R₅ comprises hydrogen, aryl, heteroaryl, cycloalkyl,             heterocyclyl, alkyl, alkenyl, alkynyl, -alkylene-aryl,             -alkylene-heteroaryl, -alkylene-heterocyclyl,             -alkylene-cycloalkyl, fused cycloalkylaryl, fused             cycloalkylheteroaryl, fused heterocyclylaryl, fused             heterocyclylheteroaryl; -alkylene-fused cycloalkylaryl,             -alkylene-fused cycloalkylheteroaryl, -alkylene-fused             heterocyclylaryl, or -alkylene-fused heterocyclylheteroaryl; -   R₃ comprises hydrogen or an alkyl group; and -   R₁₀₂ and R₁₀₄ independently comprise     -   a) —H;     -   b) -alkyl;     -   c) -aryl;     -   d) -heteroaryl;     -   e) -alkylene-heteroarylaryl;     -   f) -alkylene-aryl;     -   g) -alkylene-W₂—R₁₈;     -   h) —NR₂₃R₂₄;     -   i) —Y₄—NH—C(═NR₂₅)NR₂₃R₂₄,     -   j) —Y₄—C(═NR₂₅)NR₂₃R₂₄; or     -   k) —Y₄—Y₅-A₂;         -   wherein             -   W₂ comprises —CH₂—, —O—, —N(H), —S—, SO₂—, —CON(H)—,                 —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—,                 —NHSO₂NH—, —O—S(O)₂—, —O—CO—,

-   -   -   -   -   wherein R₁₉ and R₂₀ independently comprise hydrogen,                     aryl, alkyl, -alkylene-aryl, alkoxy, or                     -alkylene-O-aryl; and

            -   R₁₈ comprises aryl, alkyl, -alkylene-aryl,                 -alkylene-heteroaryl, and -alkylene-O-aryl;

            -   Y₅ comprises a direct bond, —CH₂—, —O—, —N(H), —S—,                 SO₂—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—,                 —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—CO—,

-   -   -   -   -   wherein R₂₇ and R₂₆ independently comprise aryl,                     alkyl, -alkylene-aryl, alkoxy, or -alkyl-O-aryl;

            -   Y₄ comprises                 -   a) -alkylene;                 -   b) -alkenylene;                 -   c) -alkynylene;                 -   d) -arylene;                 -   e) -heteroarylene;                 -   f) -cycloalkylene;                 -   g) -heterocyclylene;                 -   h) -alkylene-arylene;                 -   i) -alkylene-heteroarylene;                 -   j) -alkylene-cycloalkylene;                 -   k) -alkylene-heterocyclylene;                 -   l) -arylene-alkylene;                 -   m) -heteroarylene-alkylene;                 -   n) -cycloalkylene-alkylene;                 -   o) -heterocyclylene-alkylene;                 -   p) —O—;                 -   q) —S—;                 -   r) —S(O₂)—; or                 -   s) —S(O)—;                 -    wherein said alkylene groups may optionally contain                     one or more O, S, S(O), or SO₂ atoms;

            -   A₂ comprises                 -   a) heterocyclyl, fused arylheterocyclyl, or fused                     heteroarylheterocyclyl, containing at least one                     basic nitrogen atom,                 -   b) -imidazolyl, or                 -   c) -pyridyl;

            -   R₂₃, R₂₄, and R₂₅ independently comprise hydrogen, aryl,                 heteroaryl, -alkylene-heteroaryl, alkyl, -alkylene-aryl,                 -alkylene-O-aryl, or -alkylene-O-heteroaryl; and R₂₃ and                 R₂₄ may be taken together to form a ring having the                 formula —(CH₂)_(s)—X₃—(CH₂)_(t)— bonded to the nitrogen                 atom to which R₂₃ and R₂₄ are attached                 -   wherein                 -    s and t are, independently, 1, 2, 3, or 4;                 -    X₃ comprises direct bond, —CH₂—, —O—, —S—, —S(O₂)—,                     —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—,                     —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

-   -   -   -   -    wherein R₂₈ and R₂₉ independently comprise                     hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl,                     or -alkylene-heteroaryl;

-   wherein     -   the alkyl and/or aryl groups of R₁₀₂ and R₁₀₄ may be optionally         substituted 1-4 times with a substituent group, wherein said         substituent group(s) or the term substituted refers to a group         comprising:         -   a) halogen;         -   b) perhaloalkyl;         -   c) alkyl;         -   d) cyano;         -   e) alkyloxy;         -   f) aryl; or         -   g) aryloxy.

In a group of preferred embodiments of the compound of Formula (Ib), R₁ comprises a hydrogen, methyl, ethyl, propyl, butyl, iso-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-butenyl, tert-butyl, 3-cyclohexyl-propyl, 3-phenoxy-propyl, methoxymethyl, 4-fluoro-phenyl, 3-(4-chlorophenoxy)-propyl, 2,4,4-trimethyl-pentyl, 1-ethyl-propyl, 1-propyl-butyl, benzyloxymethyl, 2-cyclopropy-ethyl, 2-phenyl-ethyl, 4-tert-butylphenoxymethyl, 4-tert-butylcyclohexyl, 4-ethylcyclohexyl, 4-butylcyclohexyl, 3-methoxycarbonyl -1-propyl, or 2-(pyridin-3-yl)-ethyl group, and R₃ comprises hydrogen.

In another group of preferred embodiments of the compound of Formula (Ib), R₁₀₂ and R₁₀₄ independently comprise 2-(4-chlorophenyl)-ethyl, 3-(N,N′-diethylamino)-propyl, 2-amino-ethyl, 2-(N-methyl-N′-pyridin-4-yl-amino)-ethyl, 2-(N-ethyl-N′-pyridin-4-yl-amino)-ethyl, 2-(N-pyridin-4-yl-amino)-ethoxy, 4-(4-amino-pyridin-3-yl-oxy), 4-(pyridin-4-yl)-amino, 2-(N,N′-bis-pyridin-2-ylmethyl-amino)-ethyl, 2-(guanidinyl)-ethyl, 2-[4-(pyridin-4-yl)-piperazin-1-yl]-2-oxo-ethyl, 2-(N-methyl-N′-3-methylpyridin-4-yl-amino)-ethyl, 4-hydroxy-pyrrolidin-2-ylmethyl, 4-amino-3,5-dimethyl-pyrrolidin-2-ylmethyl, dibenzofuran-2-yl, 3-(piperazin-1-yl)-propyl, piperazin-4-yl, 5-(piperazin-1-yl)-pentyl, 3-(N,N′-dimethylamino)-propyl, 3-fluoro-4-trifluoromethyl-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 4-phenyl-phenyl, 3-trifluoromethoxy-phenyl, 4-trifluoromethyl-benzyl, 3,4-dichloro-phenyl, 2,4-dichloro-phenyl, 1-ethyl-piperidin-3-yl, benzyl, (1-ethyl-piperidin-3-yl)-methyl, 4-phenoxy-benzyl, 4-benzyloxy-benzyl, 2-benzenesulfonylmethyl-benzyl, 3,4,5-trimethoxybenzyl, 2-(pyrrolidin-1-yl)-ethyl, 2-(piperidin-1-yl)-ethyl, 2,2′-dimethyl-3-(N,N′-dimethylamino)-propyl, 2-(N,N′-diisopropylamino)-ethyl, 3-(2,6-dichlorophenyl)-4-methyl-isoxazol-5-ylmethyl, 4-bromo-benzyl, 4-chlorophenyl, 4-{(1-ethyl-piperidin-4-yl)-methylamino}-phenyl, 3,3-diphenylpropyl, 3,3-Bis-(4-fluorophenyl)-propyl, 3,3-Bis-(4-chlorophenyl)-allyl, 4-(4-chlorophenoxy)-naphthalenyl, 4-[2-(biphenyl-4-yl)-acetamido]-phenyl, 2-(9H-carbazole)-ethyl, 4-methoxyphenyl, 4-tert-butyl-phenyl, or naphthylen-2-ylmethyl.

In another group of preferred embodiments of the compound of Formula (Ib), R₁ comprises -alkyl, -alkylene-cycloalkylene-alkyl, -cycloalkyl, -heterocyclyl, -alkylene-cycloalkyl, -alkylene-heteroaryl, -alkylene-heterocyclyl, or -alkylene-heterocyclylene-alkyl; R₃ comprises hydrogen; R₁₀₂ comprises -aryl or -alkylene-aryl substituted with at least one of a halogen, a perhaloalkyl, or an alkoxy group; and R₁₀₄ comprises —Y₄—NR₂₃R₂₄ or —Y₄—Y₅-A₂.

In another group of preferred embodiments of the compound of Formula (Ib), R₁ comprises -heterocyclyl, heterocyclylene-heteroaryl, -alkylene-cycloalkyl, -alkylene-heteroaryl, -alkylene-heterocyclyl, or -alkylene-heterocyclylene-alkyl; R₃ comprises hydrogen; and R₁₀₂ and R₁₀₄ independently comprise -aryl or -alkylene-aryl, wherein the alkyl or ary groups are optionally substituted with at least one of a halogen, a perhaloalkyl, or an alkoxy group, and wherein at least one of R₁₀₂ and R₁₀₄ comprise —Y₄—NR₂₃R₂₄ or —Y₄—Y₅-A₂, wherein Y₄ comprises alkylene.

In a preferred embodiment, the compound of Formula (I) comprises a compound of the Formula (Ic)

wherein

-   R₁ comprises -hydrogen, -aryl, -heteroaryl, -cycloalkyl,     -heterocyclyl, -alkyl, -alkenyl, -alkynyl, -alkylene-aryl,     -alkylene-heteroaryl, -alkylene-heterocyclyl, -alkylene-cycloalkyl,     -fused cycloalkylaryl, -fused cycloalkylheteroaryl, -fused     heterocyclylaryl, -fused heterocyclylheteroaryl, -alkylene-fused     cycloalkylaryl, -alkylene-fused cycloalkylheteroaryl,     -alkylene-fused heterocyclylaryl, -alkylene-fused     heterocyclylheteroaryl, or -G₁-G₂-G₃-R₅     -   wherein         -   G₁ and G₃ independently comprise alkylene, alkenylene,             alkynylene, cycloalkylene, heterocyclylene, arylene,             heteroarylene, (aryl)alkylene, (heteroaryl) alkylene,             (aryl)alkenylene, (heteroaryl)alkenylene, or a direct bond;         -   G₂ comprises —O—, —S—, —S(O)—, —N(R₆)—, —S(O)₂—, —C(O)—,             —CO₂—, —C(O)N(R₆)—, N(R₆)C(O)—, —S(O₂)N(R₆)—, N(R₆)S(O₂)—,             —O-alkylene-C(O)—, —(O)C-alkylene-O—, —O-alkylene-,             -alkylene-O—, alkylene, alkenylene, alkynylene,             cycloalkylene, heterocyclylene, arylene, heteroarylene,             fused cycloalkylaryl, fused cycloalkylheteroaryl, fused             heterocyclylaryl, fused heterocyclylheteroaryl, or a direct             bond, wherein R₆ comprises hydrogen, aryl, alkyl,             -alkylene-aryl, alkoxy, or -alkylene-O-aryl; and         -   R₆ comprises hydrogen, aryl, heteroaryl, cycloalkyl,             heterocyclyl, alkyl, alkenyl, alkynyl, -alkylene-aryl,             -alkylene-heteroaryl, -alkylene-heterocyclyl,             -alkylene-cycloalkyl, fused cycloalkylaryl, fused             cycloalkylheteroaryl, fused heterocyclylaryl, fused             heterocyclylheteroaryl; -alkylene-fused cycloalkylaryl,             -alkylene-fused cycloalkylheteroaryl, -alkylene-fused             heterocyclylaryl, or -alkylene-fused heterocyclylheteroaryl; -   R₂ comprises     -   a) -hydrogen,     -   b) -aryl,     -   c) -heteroaryl,     -   d) -cycloalkyl,     -   e) -heterocyclyl;     -   f) -alkyl,     -   g) -alkenyl,     -   h) -alkynyl,     -   i) -alkylene-aryl,     -   j) -alkylene-heteroaryl,     -   k) -alkylene-heterocyclyl,     -   l) -alkylene-cycloalkyl;     -   m) fused cycloalkylaryl,     -   n) fused cycloalkylheteroaryl,     -   o) fused heterocyclylaryl,     -   p) fused heterocyclylheteroaryl;     -   q) -alkylene-fused cycloalkylaryl,     -   r) -alkylene-fused cycloalkylheteroaryl,     -   s) -alkylene-fused heterocyclylaryl, or     -   t) -alkylene-fused heterocyclylheteroaryl, -   R₁₁₁, R₁₁₂, R₁₁₃ and R₁₁₄ independently comprise     -   a) -hydrogen,     -   b) -halogen,     -   c) -hydroxyl,     -   d) -cyano,     -   e) -carbamoyl,     -   f) -carboxyl,     -   g) —Y₈-alkyl,     -   h) —Y₈-aryl,     -   i) —Y₈-heteroaryl,     -   j) —Y₈-alkylene-aryl,     -   k) —Y₈-alkylene-heteroaryl,     -   l) —Y₈-alkylene-W₃—R₄₀,     -   m) —Y₅—Y₆—NR₃₃R₃₄,     -   n) —Y₅—Y₆—NH—C(═NR₃₅)NR₃₃R₃₄,     -   o) —Y₅—Y₆—C(═NR₃₅)NR₃₃R₃₄, or     -   p) —Y₅—Y₆—Y₇-A₄;         -   wherein             -   Y₅ and Y₇ independently comprise a direct bond, —CH₂—,                 —O—, —N(H), —S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—,                 —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—CO—,

-   -   -   -   -   wherein R₃₆ and R₃₇ independently comprise aryl,                     alkyl, -alkylene-aryl, alkoxy, or -alkyl-O-aryl;

            -   Y₆ comprises                 -   a) alkylene;                 -   b) alkenylene;                 -   c) alkynylene;                 -   d) arylene;                 -   e) heteroarylene;                 -   f) cycloalkylene;                 -   g) heterocyclylene;                 -   h) alkylene-arylene;                 -   i) alkylene-heteroarylene;                 -   j) alkylene-cycloalkylene;                 -   k) alkylene-heterocyclylene;                 -   l) arylene-alkylene;                 -   m) heteroarylene-alkylene;                 -   n) cycloalkylene-alkylene;                 -   o) heterocyclylene-alkylene;                 -   p) —O—;                 -   q) —S—;                 -   r) —S(O₂)—; or                 -   s) —S(O)—;                 -   wherein said alkylene groups may optionally contain                     one or more O, S, S(O), or SO₂ atoms;

            -   A₄ comprises                 -   a) heterocyclyl, fused arylheterocyclyl, or fused                     heteroarylheterocyclyl, containing at least one                     basic nitrogen atom,                 -   b) -imidazolyl, or                 -   c) -pyridyl;

            -   R₃₃, R₃₄ and R₃₅ independently comprise hydrogen, aryl,                 heteroaryl, alkyl, -alkylene-aryl, or -alkylene-O-aryl;                 and R₃₃ and R₃₄ may be taken together to form a ring                 having the formula —(CH₂)_(u)—X₄—(CH₂)_(v)— bonded to                 the nitrogen atom to which R₃₃ and R₃₄ are attached,                 -   wherein                 -    u and v are, independently, 1, 2, 3, or 4;                 -    X₄ comprises a direct bond, —CH₂—, —O—, —S—,                     —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—,                     —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

-   -   -   -   -    wherein R₃₆ and R₃₇ independently comprise                     hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl,                     or -alkylene-heteroaryl;

            -   Y₈ and W₃ independently comprise —CH₂—, —O—, —N(H), —S—,                 SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—,                 —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—CO—,

-   -   -   -   -   wherein R₄₁ and R₄₂ independently comprise aryl,                     alkyl, -alkylene-aryl, alkoxy, or -alkyl-O-aryl; and

            -   R₄₀ comprises hydrogen, aryl, alkyl, -alkylene-aryl,                 -alkylene-heteroaryl, and -alkyene-O-aryl;

-   wherein at least one of R₁₁₁, R₁₁₂, R₁₁₃, and R₁₁₄ comprise a group     of the formula —Y₅—Y₆—NR₃₃R₃₄, —Y₅—Y₆—NH—C(═NR₃₅)NR₃₃R₃₄,     —Y₅—Y₆—C(═NR₃₅)NR₃₃R₃₄, or —Y₅—Y₆—Y₇-A₄.

In one group of preferred embodiments of the compound of Formula (Ic), R₂ comprises hydrogen or alkyl.

In another group of preferred embodiments of the compound of Formula (Ic), R₁ comprises a phenyl group substituted by one or more substituents comprising

-   -   a) —Y₂-alkyl;     -   b) —Y₂-aryl;     -   c) —Y₂-heteroaryl;     -   d) —Y₂-alkylene-heteroarylaryl;     -   e) —Y₂-alkylene-aryl;     -   f) —Y₂-alkylene-W₂—R₁₈;     -   g) —Y₃—Y₄—NR₂₃R₂₄     -   h) —Y₃—Y₄—NH—C(═NR₂₅)NR₂₃R₂₄     -   i) —Y₃—Y₄—C(═NR₂₅)NR₂₃R₂₄     -   j) —Y₃—Y₄—Y₅-A₂         -   wherein             -   Y₂ and W₂ independently comprise —CH₂—, —O—, and             -   R₁₈ comprises aryl, alkyl, -alkylene-aryl,                 -alkylene-heteroaryl, or -alkylene-O-aryl;             -   Y₃ and Y₅ independently comprise a direct bond, —CH₂—,                 —O—, —N(H), —S—, SO₂—, —C(O)—, —CON(H)—, —NHC(O)—,                 —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—,                 —O—CO—,

-   -   -   -   -   wherein R₂₇ and R₂₆ independently comprise aryl,                     alkyl, -alkylene-aryl, alkoxy, or -alkyl-O-aryl;

            -   Y₄ comprises                 -   a) -alkylene;                 -   b) -alkenylene;                 -   c) -alkynylene;                 -   d) -arylene;                 -   e) -heteroarylene;                 -   f) -cycloalkylene;                 -   g) -heterocyclylene;                 -   h) -alkylene-arylene;                 -   i) -alkylene-heteroarylene;                 -   j) -alkylene-cycloalkylene;                 -   k) -alkylene-heterocyclylene;                 -   l) -arylene-alkylene;                 -   m) -heteroarylene-alkylene;                 -   n) -cycloalkylene-alkylene;                 -   o) -heterocyclylene-alkylene;                 -   p) —O—;                 -   q) —S—;                 -   r) —S(O₂)—; or                 -   s) —S(O)—;                 -    wherein said alkylene groups may optionally contain                     one or more O, S, S(O), or SO₂ atoms;

            -   A₂ comprises                 -   a) heterocyclyl, fused arylheterocyclyl, or fused                     heteroarylheterocyclyl, containing at least one                     basic nitrogen atom,                 -   b) -imidazolyl, or                 -   c) -pyridyl;

            -   R₂₃, R₂₄, and R₂₅ independently comprise hydrogen, aryl,                 heteroaryl, -alkylene-heteroaryl, alkyl, -alkylene-aryl,                 -alkylene-O-aryl, or -alkylene-O-heteroaryl; and R₂₃ and                 R₂₄ may be taken together to form a ring having the                 formula —(CH₂)_(s)—X₃—(CH₂)_(t)— bonded to the nitrogen                 atom to which R₂₃ and R₂₄ are attached                 -   wherein                 -    s and t are, independently, 1, 2, 3, or 4;                 -   X₃ comprises direct bond, —CH₂—, —O—, —S—, —S(O₂)—,                     —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—,                     —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

-   -   -   -   -    wherein R₂₈ and R₂₉ independently comprise                     hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl,                     or -alkylene-heteroaryl.

In another group of preferred embodiments of the compound of Formula (Ic), R₁ comprises 2-methoxy-3,5-dimethyoxy-phenyl, 3-(4-tert-butyl-phenoxy)-phenyl, 4-[3-(N,N′-diethylamino)-propoxy]-phenyl, 4-[3-(N,N′-dimethylamino)-propoxy]-phenyl, 4-[(pyrrolidin-1-yl)-ethoxy]-phenyl, 3-[(pyrrolidin-1-yl)-ethoxy]-phenyl, 2-[(pyrrolidin-1-yl)-ethoxy]-phenyl, 3-(naphthalen-2-yloxy)-phenyl, 4-biphenyl, 3-(3,3-dimethylbutoxy)-phenyl, 3-(phenoxy)-phenyl, 3-(3,4-dichloro-phenoxy)-phenyl, 3-(3,5-dichloro-phenoxy)-phenyl, 4-tert-butyl-phenyl, 4-(dibutylamino)-phenyl, 4-[2-(4-methoxy-phenyl)-ethoxy]-phenyl, 2-naphthyl, 2-benzofuranyl, 3-(3-trifluoromethyl-phenoxy)-phenyl, 4-chloro-phenyl, 2-benzhydryl, 4-isopropoxy-phenyl, 3-(4-tertbutyl-phenoxy)-phenyl, 4-[2-(4-chloro-phenyl)-ethoxy]-phenyl, 3-[2-(4-chloro-phenyl)-ethoxy]-phenyl, 2-{3-[2-(4-chloro-phenyl)-ethoxy]-phenyl]-ethyl, 2-{4-[2-(4-methoxy-phenyl)-ethoxy]-phenyl}-ethyl, or 2-[3-(N,N-diethylamino)-propoxy)]-4-[2-(4-chloro-phenyl)-ethoxy]-phenyl.

In another group of preferred embodiments of the compound of Formula (Ic), R₁ comprises 4-[2-(4-chloro-phenyl)-ethoxy]-phenyl, 3-[2-(4-chloro-phenyl)-ethoxy]-phenyl, 2-{3-[2-(4-chloro-phenyl)-ethoxy]-phenyl]-ethyl, 2-{4-[2-(4-methoxy-phenyl)-ethoxy]-phenyl}-ethyl, or 2-[3-(N,N-diethylamino)-propoxy)]-4-[2-(4-chloro-phenyl)-ethoxy]-phenyl.

In another group of preferred embodiments of the compound of Formula (Ic), R₁₁₁, R₁₁₂ and R₁₁₄ comprise hygrogen; and R₁₁₃ comprises —Y₃—Y₄—NR₂₃R₂₄, or —Y₃—Y₄—Y₅-A₂.

In another group of preferred embodiments of the compound of Formula (Ic), R₁ comprises 4-[2-(4-chloro-phenyl)-ethoxy]-phenyl, 3-[2-(4-chloro-phenyl)-ethoxy]-phenyl, 2-{3-[2-(4-chloro-phenyl)-ethoxy]-phenyl]-ethyl, 2-{4-[2-(4-methoxy-phenyl)-ethoxy]-phenyl}-ethyl, or 2-[3-(N,N-diethylamino)-propoxy)]-4-[2-(4-chloro-phenyl)-ethoxy]-phenyl; R₂ comprises alkyl; R₁₁₂ and R₁₁₄ comprise hygrogen; and R₁₁₁ and R₁₁₃ comprise —Y₃—Y₄—NR₂₃R₂₄, or —Y₃—Y₄—Y₅-A₂.

In the compounds of Formula (I), the various functional groups represented should be understood to have a point of attachment at the functional group having the hyphen. In other words, in the case of —C₁₋₆ alkylaryl, it should be understood that the point of attachment is the alkyl group; an example would be benzyl. In the case of a group such as —C(O)—NH—C₁₋₆ alkylaryl, the point of attachment is the carbonyl carbon.

Also included within the scope of the invention are the individual enantiomers of the compounds represented by Formula (I) above as well as any wholly or partially racemic mixtures thereof. The present invention also covers the individual enantiomers of the compounds represented by the Formula above as mixtures with diastereoisomers thereof in which one or more stereocenters are inverted.

Compounds of the present invention preferred for their high biological activity are listed by name below in Table 1.

TABLE 1 Ex. Structure Name 1

1-butyl-2-(3-cyclohexylmethoxy-phenyl)- 6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 2

{3-[3-butyl-2-(3,5-di-tert-butyl-2- methoxy-phenyl)-3H-benzimidazol-5- yloxy]-propyl}-diethyl-amine 3

(2-{3-butyl-2-[3-(4-tert-butyl-phenoxy)- phenyl]-3H-benzoimidazol-5-yloxy}- ethyl)-diisopropyl-amine 4

(3-{4-[1-butyl-6-(4-tert-butyl-phenoxy)- 1H-benzimidazol-2-yl]-phenoxy}- propyl)-diethyl-amine 5

1-butyl-6-(4-tert-butyl-phenoxy)-2-[3- (2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H- benzimidazole 6

1-butyl-6-(4-tert-butyl-phenoxy)-2-[2- (2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H- benzimidazole 7

1-butyl-2-[3-(naphthalen-2-yloxy)- phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 8

2-biphenyl-4-yl-1-butyl-6-(2-piperazin- 1-yl-ethoxy)-1H-benzimidazole 9

1-butyl-6-(4-tert-butyl-phenoxy)-2-[4-(2- pyrrolidin-1-yl-ethoxy)-phenyl]-1H- benzimidazole 10

1-butyl-2-[3-(3,3-dimethyl-butoxy)- phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 11

1-butyl-6-(4-fluoro-3-trifluoromethyl- phenoxy)-2-[4-(2-pyrrolidin-1-yl- ethoxy)-phenyl]-1H-benzimidazole 12

1-butyl-2-(3-phenoxy-phenyl)-6-(2- piperazin-1-yl-ethoxy)-1H- benzoimidazole 13

1-butyl-2-[3-(4-tert-butyl-phenoxy)- phenyl]-6-(2-piperidin-1-yl-ethoxy)-1H- benzimidazole 14

1-butyl-2-[3-(3,4-dichloro-phenoxy)- phenyl]-6-(2-piperidin-1-yl-ethoxy)-1H- benzimidazole 15

1-butyl-6-[2-(4-chloro-phenyl)-ethoxy]- 2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]- 1H-benzimidazole 16

1-butyl-2-[3-(3,5-dichloro-phenoxy)- phenyl]-6-(2-piperidin-1-yl-ethoxy)-1H- benzimidazole 17

1-butyl-2-(4-tert-butyl-phenyl)-6-(2- piperazin-1-yl-ethoxy)-1H- benzoimidazole 18

dibutyl-{4-[1-butyl-6-(3-diethylamino- propoxy)-1H-benzimidazol-2-yl]- phenyl}-amine 19

(2-{3-butyl-2-[3-(3,5-dichloro-phenoxy)- phenyl]-3H-benzoimidazol-5-yloxy}- ethyl)-diisopropyl-amine 20

{3-[3-butyl-2-(4-tert-butyl-phenyl)-3H- benzimidazol-5-yloxy]-propyl}-diethyl- amine 21

1-butyl-2-(3,5-di-tert-butyl-2-methoxy- phenyl)-6-(2-piperazin-1-ylethoxy)-1H- benzoimidazole 22

{3-[3-butyl-2-(3-{4-[2-(4-methoxy- phenyl)-ethoxy]-phenyl}-propyl)-3H- benzimidazol-5-yloxy]-propyl}-diethyl- amine 23

1-butyl-2-naphthalen-2-yl-6-(2- piperazin-1-yl-ethoxy)-1H- benzimidazole 24

(2-{3-butyl-2-[3-(4-tert-butyl-phenoxy)- phenyl]-3H-benzoimidazol-5-yloxy}- ethyl)-dimethyl-amine 25

2-benzofuran-2-yl-1-butyl-6-(2-piperazin- 1-yl-ethoxy)-1H-benzimidazole 26

1-butyl-6-(2-piperazin-1-yl-ethoxy)-2- [3-(3-trifluoromethyl-phenoxy)-phenyl]- 1H-benzimidazole 27

2-benzhydryl-1-butyl-6-(2-piperazin-1- yl-ethoxy)-1H-benzimidazole 28

1-Butyl-2-(4-chloro-phenyl)-6-(2- piperazin-1-yl-ethoxy)-1H- benzoimidazole 29

{3-[3-Butyl-2-(4-isopropoxy-phenyl)- 3H-benzoimidazol-5-yloxy]-propyl}- diethyl-amine 30

1-Butyl-6-(2-piperazin-1-yl-ethoxy)-2- [3-(4,4,4-trifluoro-butoxy)-phenyl]-1H- benzoimidazole 31

{3-[3-Butyl-2-(2,4,4-trimethyl-pentyl)- 3H-benzoimidazol-5-yloxy]-propyl}- diethyl-amine 32

Diethyl-{2-[2-piperidin-3-yl-3-(4- pyrrolidin-1-yl-butyl)-3H- benzoimidazol-5-yloxy]-ethyl}-amine 33

Diethyl-{2-[2-piperidin-4-yl-3-(4- pyrrolidin-1-yl-butyl)-3H- benzoimidazol-5-yloxy]-ethyl}-amine 34

{3-[1-Butyl-6-(3-diethylamino-propoxy)- 2-piperidin-4-yl-1H-benzoimidazol-4- yloxy]-propyl}-diethyl-amine 35

{3-[3-butyl-2-[3-(4-tert-butyl-phenoxy)- phenyl]-7-(2-pyrrolidin-1-yl-ethoxy)-3H- benzimidazol-5-yloxy]-propyl}-diethyl- amine 36

1-Butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazole 37

1-butyl-2-[3-(3-tert-butyl-phenoxy)- phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 38

2-[3-(biphenyl-4-yloxy)-phenyl]-1- butyl-6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 39

1-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-(2-piperazin-1-yl- ethoxy)-1H-benzimidazole 40

[3-(3-butyl-2-{3-[2-(4-chloro-phenyl)- ethoxy]-4-nitro-phenyl}-3H- benzimidazol-5-yloxy)-propyl]-diethyl- amine 41

[2-(3-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-3H-benzimidazol-5- yloxy)-ethyl]-diethyl-amine 42

1-butyl-2-[3-(3,5-dichloro-phenoxy)- phenyl]-6-(piperidin-4-ylmethoxy)-1H- benzoimidazole 43

1-butyl-2-{3-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-(2-piperazin-1-yl- ethoxy)-1H-benzoimidazole 44

{3-[3-butyl-2-(2-{4-[2-(4-chlorophenyl)- ethoxy]-phenyl}-ethyl)-3H- benzimidazol-5-yloxy]-propyl}-diethyl- amine 45

1-butyl-2-[3-(3,5-dichloro-phenoxy)- phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H- benzimidazole 46

1-butyl-6-[2-(4-butyl-piperazin-1-yl)- ethoxy]-2-[3-(3-trifluoromethyl- phenoxy)-phenyl]-1H-benzimidazole 47

{3-[3-butyl-2-(2-{4-[2-(4- chlorophenyl)-ethoxy]-phenyl}-ethyl)- 3H-benzimidazol-5-yloxy]-propyl}- diethyl-amine 48

(3-{3-butyl-2-[3-(4-methoxy-phenoxy)- phenyl]-3H-benzimidazol-5-yloxy}- propyl)-diethyl-amine 49

{3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]- phenyl}-6-(2-diethylamino-ethoxy)- benzimidazol-1-yl]-propyl}-diethyl- amine 50

[3-(1-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-1H-benzimidazol-4- yloxy)-propyl]-diethyl-amine 51

[3-(1-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-1H-benzimidazol-5-yl)- propyl]-diethyl-amine 52

1-butyl-2-[3-(2-isopropyl-phenoxy)- phenyl}-6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 53

{3-[3-butyl-2-(2-{4-[3-(4-methoxy- phenyl)-propoxy]-phenyl}-ethyl)-3H- benzimidazol-5-yloxy]-propyl}-diethyl- amine 54

{3-[3-butyl-2-(2-{4-[4-(4-methoxy- phenyl)-butoxy]-phenyl}-ethyl)-3H- benzimidazol-5-yloxy]-propyl}-diethyl- amine 55

[3-(3-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-3-ethoxy-phenyl}-3H- benzimidazol-5-yloxy)-propyl]-diethyl- amine 56

(3-{3-butyl-2-[3-(3-trifluoromethyl- phenoxy)-phenyl]-3H-benzimidazol-5- yloxy}-propyl)-diethyl-amine 57

1-butyl-2-[3-(4-chloro-phenoxy)- phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 58

1-butyl-2-[3-(3,4-dichloro-phenoxy)- phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 59

1-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-(piperidin-4-yloxy)- 1H-benzoimidazole 60

3-(3-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-3H-benzoimidazol-5- yloxy)-1-aza-bicyclo[2.2.2]octane 61

1-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-(2,2,6,6,-tetramethyl- piperidin-4-yloxy)-1H-benzoimidazole 62

2-[3-(4-butoxy-phenoxy)-phenyl]-1- butyl-6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 63

[3-(3-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-3H-benzimidazol-5- yloxy)-propyl]-diethyl-amine 64

{3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]- phenyl}-3-(3-methyl-butyl)-3H- benzimidazol-5-yloxy]-propyl}-diethyl- amine 65

[3-(2-{4-[2-(4-chloro-phenyl)-ethoxy]- phenyl}-3-hexyl-3H-benzimidazol-5- yloxy)-propyl]-diethyl-amine 66

{3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]- phenyl}-6-(2-diethylamino-ethoxy)- benzimidazol-1-yl]-propyl}-dimethyl- amine 67

1-butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]-6-(2- piperazin-1-ylethoxy)-1H- benzoimidazole 68

[3-(3-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-3H-benzimidazol-5- yloxy)-propyl]-diethyl-amine 69

{3-[2-(4-benzyloxy-3,5-dimethyl- phenyl)-3-butyl-3H-benzimidazol-5- yloxy]-propyl}-diethyl-amine 70

{3-[3-butyl-2-[3-(3,4-dichloro-phenoxy)- phenyl]-3H-benzimidazol-5-yloxy]- propyl}-diethyl-amine 71

1-butyl-6-[2-(4-methyl-piperazin-1-yl)- ethoxy]-2-[3-(3-trifluoromethyl- phenoxy)-phenyl]-1H-benzimidazole 72

1-butyl-6-[2-(4-isopropyl-piperazin-1-yl)- ethoxy]-2-[3-(3-trifluoromethyl- phenoxy)-phenyl]-1H-benzoimidazole 73

1-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-(3-piperazin-1-yl- propoxy)-1H-benzoimidazole 74

(3-{3-butyl-2-[3-(3,4-dichloro-phenoxy)- phenyl]-3H-benzimidazol-5-yloxy}- propyl)-diethyl-amine 75

1-butyl-2-[3-(3,4-dimethoxy-phenoxy)- phenyl]-6-(2-piperidin-4-yloxy)-1H- benzoimidazole 76

1-butyl-2-[3-(4-chloro-benzyloxy)- phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 77

1-butyl-2-[3-(3,5-dichloro-phenoxy)- phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 78

(3-{2-[2-(4-benzyloxy-phenyl)-ethyl]-3- butyl-3H-benzimidazol-5-yloxy}- propyl)-diethyl-amine 79

(3-{3-butyl-2-[2-(4-phenethyloxy- phenyl)-ethyl]-3H-benzimidazol-5- yloxy}-propyl)-diethyl-amine 80

{3-[3-butyl-2-(2-{4-[2-(4-fluoro-phenyl)- ethoxy]-phenyl}-ethyl)-3H- benzimidazol-5-yloxy]-propyl}-diethyl- amine 81

[3-(3-butyl-2-{2-[4-(4-chloro-benzyloxy)- phenyl]-ethyl}-3H-benzimidazol-5- yloxy)-propyl}-diethyl-amine 82

(3-{3-butyl-2-[4-(4-fluoro-benzyloxy)- phenyl]-3H-benzimidazol-5-yloxy}- propyl)-diethyl-amine 83

{3-[2-(3-benzyloxy-phenyl)-3-butyl-3H- benzimidazol-5-yloxy]-propyl}-diethyl- amine 84

[3-(3-butyl-2-{4-chloro-3-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-3H- benzimidazol-5-yloxy)-propyl]-diethyl- amine 85

1-butyl-2-[3-(4-tert-butyl-phenoxy)- phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H- benzimidazole 86

1-butyl-2-[4-(4-isopropyl-phenoxy)- phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 87

1-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-[3-(4-methyl- piperazin-1-yl)-propoxy]-1H- benzoimidazole 88

1-butyl-6-[2-(4-butyl-piperazin-1-yl)- ethoxy]-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-1H-benzoimidazole 89

1-butyl-2-[3-(3,4-dimethoxy-phenoxy)- phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 90

1-butyl-2-[4-(4-tert-butyl-benzyl)- phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 91

N-{4-[1-butyl-6-(3-diethylamino- propoxy)-1H-benzimidazol-2-yl]-2-[2- (4-chloro-phenyl)-ethoxy]-phenyl}-2,2- dimethyl-propioinamide 92

(3-{3-butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]-3H- benzimidazol-5-yloxy}-propyl)-diethyl- amine 93

1-butyl-2-[4-(naphthalen-2-yloxy)- phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 94

1-butyl-2-[3-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]-6- (2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 95

[3-(3-butyl-2-{4-[2-(4-methoxy-phenyl)- ethoxy]-phenyl}-3H-benzimidazol-5- yloxy)-propyl]-diethyl-amine 96

4-[1-butyl-6-(3-diethylamino-propoxy)- 1H-benzimidazol-2-yl]-2-[2-(4-chloro- phenyl)-ethoxy]-phenylamine 97

1-{4-[1-butyl-6-(3-diethylamino- propoxy)-1H-benzimidazol-2-yl]-2-[2- (4-chloro-phenyl)-ethoxy]-phenyl}-3- isopropyl-urea 98

{3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]- phenyl}-6-(2-dimethylamino-ethoxy)- benzimidazol-1-yl]-propyl}-dimethyl- amine 99

1-butyl-2-[3-(4-tert-butyl-phenoxy)- phenyl]-6-[2-(4-methyl-piperazin-1-yl)- ethoxy]-1H-benzimidazole 100

1-butyl-6-(4-cyclopentyl-phenoxy)-2- [4-(4-methyl-piperazin-1-ylmethyl)- phenyl]-1H-benzoimidazole 101

{3-[2-(4-benzyloxy-phenyl)-3- cyclopentylmethyl-3H-benzimidazol-5- yloxy]-propyl}-diethyl-amine 102

1-butyl-6-(4-butyl-phenoxy)-2-{3,5- dimethyl-4-[2-(1-methyl-pyrrolidin-2-yl)- ethoxy]-phenyl}-1H-benzoimidazole 103

1-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-(3-pyrrolidin-1-yl- propoxy)-1H-benzoimidazole 104

{3-[2-(4-benzyloxy-phenyl)-3-isobutyl- 3H-benzimidazol-5-yloxy]-propyl}- diethyl-amine 105

[3-(3-butyl-2-{3-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-3H-benzimidazol-5- yloxy)-propyl]-diethyl-amine 106

1-butyl-6-(1-butyl-piperidin-4-yloxy)-2- [3-(3,5-dichloro-phenoxy)-phenyl]-1H- benzoimidazole 107

1-butyl-2-[3-(3,5-dichloro-phenoxy)- phenyl]-6-(1-ethyl-piperidin-4-yloxy)- 1H-benzoimidazole 108

1-butyl-6-(4-fluoro-3-trifluoromethyl- phenoxy)-2-[4-(4-methyl-piperazin-1- ylmethyl)-phenyl]-1H-benzoimidazole 109

diethyl-{3-[3-isobutyl-2-(2-{4-[2-(4- methoxy-phenyl)-ethoxy]-phenyl}-ethyl)- 3H-benzimidazol-5-yloxy]-propyl}- amine 110

{3-[2-(2-{4-[2-(4-chlorophenyl)- ethoxy]-phenyl}-ethyl)-3-isobutyl-3H- benzimidazol-5-yloxy]-propyl}-diethyl- amine 111

1-butyl-6-(2-piperazin-1-yl-ethoxy)-2- [3-(3-trifluoromethyl-phenoxy)-phenyl]- 1H-benzimidazole 112

1-butyl-2-[3-(4-tert-butyl-phenoxy)- phenyl]-6-(2-pyrrolidin-1-yl-ethoxy)-1H- benzimidazole 113

1-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-[2-(4-methyl- piperazin-1-yl)-ethoxy]-1H- benzimidazole 114

{3-[2-(4-benzyloxy-phenyl)-3- cyclopentyl-3H-benzimidazol-5-yloxy)- propyl]-diethyl-amine 115

1-Butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-5-(4-methyl-piperazin- 1-ylmethyl)-1H-benzoimidazole 116

[2-(3-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-3H-benzimidazol-5- yloxy)-ethyl]-dimethyl-amine 117

[2-(3-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-3H-benzimidazol-5- yloxy)-ethyl]-diisopropyl-amine 118

1-butyl-2-[3-(3,5-dichloro-phenoxy)- phenyl]-6-[2-(4-methyl-piperazin-1-yl)- ethoxy]-1H-benzimidazole 119

(3-{1-butyl-2-[3-(4-tert-butyl-phenoxy)- phenyl]-1H-benzimidazol-4-yloxy}- propyl)-diethyl-amine 120

2-(3-butoxy-phenyl)-1-butyl-6-(2- piperazin-1-yl-ethoxy)-1H- benzimidazole 121

1-butyl-2-[3-(4-methanesulfonyl- benzyloxy)-phenyl]-6-(2-piperazin-1-yl- ethoxy)-1H-benzoimidazole 122

4′{3-[1-butyl-6-(2-piperazin-1-yl-ethoxy)- 1H-benzoimidazol-2-yl]-phenoxy}- biphenyl-4-carbonitrile 123

{3-[2-(4-benzyloxy-phenyl)-3-butyl-3H- benzimidazol-5-yloxy]-propyl}-diethyl- amine 124

1-Butyl-2-[4-(3-chloro-phenoxy)-phenyl]- 6-(2-pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 125

1-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-[2-(4-isopropyl- piperazin-1-yl)-ethoxy]-1H- benzoimidazole 126

{3-[2-(3-benzyloxy-4-methoxy-phenyl)- 3-butyl-3H-benzimidazol-5-yloxy)- propyl]-diethyl-amine 127

(3-{3-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-3H-benzimidazol-5- yloxy}-propyl)-diethyl-amine 128

{3-[3-butyl-2-(3-phenoxy-phenyl)-3H- benzimidazol-5-yloxy]-propyl}-diethyl- amine 129

1-butyl-2-[3-(3,5-dichloro-phenoxy)- phenyl]-6-[2-(4-ethyl-piperazin-1-yl)- ethoxy]-1H-benzimidazole 130

1-butyl-2-[4-(2,3-di-methoxy- phenoxy)-phenyl]-6-(2-piperazin-1- ylethoxy)-1H-benzoimidazole 131

[3-(3-butyl-2-{2-[4-(4-chloro-benzyloxy)- phenyl]-ethyl}-3H-benzimidazol-5- yloxy)-propyl]-diethyl-amine 132

(3-{3-butyl-2-[3-(4-chloro-phenoxy)- phenyl]-3H-benzimidazol-5-yloxy}- propyl)-diethyl-amine 133

{3-[2-(4-benzyloxy-phenyl)-3- isopropyl-3H-benzimidazol-5-yloxy]- propyl}-diethyl-amine 134

(2-{3-butyl-2-[3-(3-trifluoromethyl- phenoxy)-phenyl]-3H- benzoimidazol-5-yloxy}-ethyl)- diisopropyl-amine 135

1-butyl-6-[2-(4-ethyl-piperazin-1-yl)- ethoxy]-2-[3-(3-trifluoromethyl- phenoxy)-phenyl]-1H-benzimidazole 136

{3-[3-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-3H-benzimidazol-5- yloxy]-propyl}-diethyl-amine 137

(3-{2-butyl-2-[3-(4-tert-butyl-phenoxy)- phenyl]-3H-benzimidazol-5-yloxy}- ethyl)-cyclohexyl-methyl-amine 138

1-butyl-6-[2-(4-propyl-piperazin-1-yl)- ethoxy]-2-[3-(3-trifluoromethyl- phenoxy)-phenyl]-1H-benzimidazole 139

1-butyl-6-(4-butyl-phenoxy)-2-[4-(4- methyl-piperazin-1-ylmethyl)-phenyl]- 1H-benzoimidazole 140

1-butyl-2-[3-(4-tert-butyl-phenoxy)- phenyl}-6-(2-morpholin-4-yl-ethoxy)- 1H-benzimidazole 141

4-[1-butyl-6-(3-diethylamino-propoxy)- 1H-benzimidazol-2-yl]-2-phenethyloxy- phenylamine 142

{2-[2-(4-benzyloxy-phenyl)-3- phenethyl-3H-benzimidazol-5-yloxy]- ethyl}-diethyl-amine 143

{3-[3-butyl-2-(4-phenoxy-phenyl)- 3H-benzimidazol-5-yloxy]-propyl}- diethyl-amine 144

3-[4-(2-{3-butyl-2-[3-(3,4-dichloro- phenoxy)-phenyl]-3H-benzimidazol-5- yloxy}-ethyl)-piperazin-1-yl]-propan-1- ol 145

1-butyl-6-(2-pyrrolidin-1-yl-ethoxy)- 2-[3-(3-trifluoromethyl-phenoxy)- phenyl]-1H-benzimidazole 146

{2-[2-[4-[2-(4-chloro-phenyl)-ethoxy]- phenyl}-6-(2-diethylamino-ethoxy)- benzimidazol-1-yl]-ethyl}-dimethyl- amine 147

1-butyl-6-(2-morpholin-4-yl-ethoxy)- 2-[3-(3-trifluoromethyl-phenoxy)- phenyl]-1H-benzimidazole 148

1-butyl-2-[3-(3,5-dichloro-phenoxy)- phenyl]-6-(1-methyl-piperidin-4-yloxy)- 1H-benzoimidazole 149

N′-[3-butyl-2-(2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-ethyl)-3H- benzimidazol-5-yl]-N,N-diethyl- propane-1,3-diamine 150

1-butyl-2-[3-(2,4-dichloro-phenoxy)- phenyl]-6-(2-pyrrolidin-1-yl-ethoxy)-1H- benzimidazole 151

1-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-(2-morpholin-4-yl- ethoxy)-1H-benzimidazole 152

1-butyl-6-(2-piperazin-1-yl-ethoxy)-2- [4-(4-trifluoromethyl-phenoxy)-phenyl]- 1H-benzoimidazole 153

2-[4-(biphenyl-4-yloxy)-phenyl]-1-butyl- 6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 154

1-butyl-2-[3-(3,5-dichloro-phenoxy)- phenyl]-6-(2-morpholin-4-yl-ethoxy)- 1H-benzimidazole 155

1-butyl-2-[3-(3,4-dimethoxy-phenoxy)- phenyl]-6-(2-piperazin-1-yl-ethoxy)- 1H-benzoimidazole 156

1-butyl-2-[3-(4-tert-butyl-phenoxy)- phenyl]-5-(1H-imidazol-4-ylmethoxy)- 1H-benzoimidazole 157

{3-[2-(2-benzyloxy-phenyl)-3-butyl- 3H-benzimidazol-5-yloxy]-propyl}- diethyl-amine 158

{3-[1-Butyl-6-(3-diethylamino- propoxy)-2-piperidin-4-yl-1H- benzoimidazol-4-yloxy]-propyl}- diethyl-amine 159

(2-{2-[2-(4-Benzyloxy-phenyl)-ethyl]- 3-phenethyl-3H-benzoimidazol-5- yloxy}-ethyl)-diethyl-amine 160

[3-(3-Butyl-2-{3-[4-(4-fluoro- benzyloxy)-phenyl]-propyl}-3H- benzoimidazol-5-yloxy)-propyl]-diethyl- amine 161

[3-(4-Benzyloxy-phenyl)-propyl]-[1- butyl-6-(3-diethylamino-propoxy)-1H- benzoimidazol-2-yl]-amine 162

{3-[3-Butyl-2-(3-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-propyl)-3H- benzoimidazol-5-yloxy]-propyl}- diethyl-amine 163

1-Butyl-2-[3-(3,5-dichloro-phenoxy)- phenyl]-6-(2-imidazol-1-yl-ethoxy)-1H- benzoimidazole 164

1-[4-(2-{3-Butyl-2-[3-(3- trifluoromethyl-phenoxy)-phenyl]-3H- benzoimidazol-5-yloxy}-ethyl)- piperazin-1-yl]-ethanone 165

N-[3-Butyl-2-(2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-ethyl)-3H- benzoimidazol-5-yl]-N-(3- diethylamino-propyl)-N′,N′-diethyl- propane-1,3-diamine 166

{3-[1-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-(3-diethylamino- propoxy)-1H-benzimidazol-4-yl]- propyl}-diethyl-amine 167

{3-[1-Butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-yloxy]- propyl}-diethyl-amine 168

{3-[2-(2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-ethyl)-6-(3- diethylamino-propoxy)-3H- benzimidazol-4-yloxy]-propyl}-diethyl- amine 169

{3-[1-Butyl-2-[4-(4-chloro-3- trifluoromethyl-phenoxy)-phenyl]-6- (3-diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}- diethyl-amine 170

(3-{1-Butyl-6-(3-diethylamino- propoxy)-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]- 1H-benzoimidazol-4-yloxy}-propyl)- diethyl-amine 171

{3-[2-[3-(3,5-Dichloro-phenoxy)- phenyl]-6-(3-diethylamino-propoxy)- 1H-benzoimidazol-4-yloxy}-propyl}- diethyl-amine 172

1-Butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-4,6-bis-(2-pyrrolidin-1- yl-ethoxy)-1H-benzoimidazole 173

{3-[2-[3-(3,4-Dichloro-phenoxy)- phenyl]-6-(3-diethylamino-propoxy)- 1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 174

(3-{6-(3-diethylamino-propoxy)-2-[3- (3-trifluoromethyl-phenoxy)-phenyl]- 1H-benzimidazol-4-yloxy}-propyl)- diethyl-amine 175

{3-[1-Butyl-2-[3-(3,4-dichloro- phenoxy)-phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-yloxy]- propyl}-diethyl-amine 176

{3-[2-[3-(4-Chloro-phenoxy)-phenyl]- 6-(3-diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}-diethyl- amine 177

{3-[1-Butyl-2-[3-(4-chloro-phenoxy)- phenyl]-6-(3-diethylamino-propoxy)- 1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 178

{3-[1-Butyl-6-(3-diethylamino- propoxy)-2-(3-p-tolyloxy-phenyl)-1H- benzoimidazol-4-yloxy]-propyl}- diethyl-amine 179

{3-[1-Butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4- yloxy]-propyl}-diethyl-amine 180

1-Butyl-2-[3-(4-tert-butyl-phenoxy)- phenyl]-4,6-bis-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazole 181

{3-[3-Butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-7-(2-pyrrolidin-1-yl- ethoxy)-3H-benzoimidazol-5-yloxy]- propyl}-diethyl-amine 182

(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[4-(3-fluoro-phenoxy)- phenyl]-1H-benzimidazol-4-yloxy}- propyl)-diethyl-amine 183

{3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]- phenyl}-6-(3-diethylamino-propoxy)- 1-isopropyl-1H-benzimidazol-4- yloxy]-propyl}-diethyl-amine 184

{3-[1-Butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazol-4-yloxy]- propyl}-diethyl-amine 185

2-{4-[1-butyl-4,6-bis-(3- diethylamino-propoxy)-1H- benzimidazol-2-yl-phenoxy}-benzoic acid methyl ester 186

{3-[2-[4-(biphenyl-4-yloxy)-phenyl]- 1-butyl-6-(3-diethylamino-propoxy)- 1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 187

{3-[2-[4-(3,5-Bis-trifluoromethyl- phenoxy)-phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-yloxy]- propyl}-diethyl-amine 188

{3-[1-butyl-2-[4-(4-chloro- benzylsulfanyl)-phenyl]-6-(3- diethylamino-propoxy)-1H- benzimidazol-4-yloxy]-propyl}-diethyl- amine 189

{3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]- phenyl}-6-(3-diethylamino-propoxy)- 3H-benzimidazol-4-yloxy]-propyl}- diethyl-amine 190

[3-{1-butyl-6-(3-diethylamino- propoxy)-2-[3-(3-trifluoromethyl- phenoxy)-phenyl]-1H-benzimidazol- 4-yloxy}-propyl)-diethyl-amine 191

[3-(1-butyl-6-(3-diethylamino- propoxy)-2-{4-[2-(4-fluoro-phenyl)- ethoxy]-phenyl}-1H-benzimidazol-4- yloxy}-propyl)-diethyl-amine 192

(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[4-(3-trifluoromethyl- phenoxy)-phenyl]-1H-benzimidazol- 4-yloxy}-propyl)-diethyl-amine 193

{3-[2-[3-(4-tert-Butyl-phenoxy)- phenyl]-6-(3-diethylamino-propoxy)- 1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 194

(3-{1-Butyl-6-(3-diethylamino-propoxy)- 2-[4-(4-fluoro-3-trifluoromethyl- phenoxy)-2-trifluoromethyl-phenyl]- 1H-benzoimidazol-4-yloxy}- propyl)-diethyl-amine 195

{3-[1-Butyl-2-[4-chloro-2-(4-chloro-3- trifluoromethyl-phenoxy)-phenyl]-6- (3-diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}- diethyl-amine 196

2-[3-(4-Chloro-phenoxy)-phenyl]- 4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 197

1-Butyl-2-[3-(4-chloro-phenoxy)- phenyl]-4,6-bis-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazole 198

{3-[3-butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]-7- (2-pyrrolidin-1-yl-ethoxy)-3H- benzimidazol-5-yloxy]-propyl}-diethyl- amine 199

{2-[1-butyl-2-[3-(4-tert-butyl-phenoxy)- phenyl]-6-(2-diisopropylamino-ethoxy)- 1H-benzimidazol-4-yloxy]-ethyl}- diethyl-amine 200

{3-[2-[4-(3,5-Bis-trifluoromethyl- phenoxy)-phenyl]-1-butyl-6-(3- diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}-diethyl- amine 201

{3-[2-[4-(3,5-Bis-trifluoromethyl- phenoxy)-phenyl]-1-butyl-6-(3- diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}-diethyl- amine 202

(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[4-(4-methoxy-phenoxy)- phenyl]-1H-benzimidazol-4-yloxy}- propyl)-diethyl-amine 203

1-Butyl-2-[4-(4-chloro-3- trifluoromethyl-phenoxy)-phenyl]- 4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 204

2-{4-[2-(4-Chloro-phenyl)-ethoxy]- phenyl}-4,6-bis-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazole 205

1-Butyl-2-[4-(4-tert-butyl-phenoxy)- phenyl]-4,6-bis-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazole 206

1-Butyl-2-[4-(4-fluoro-3-trifluoromethyl- phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin- 1-yl-ethoxy)-1H-benzoimidazole 207

{3-[1-Butyl-2-[4-(3-chloro-phenoxy)- phenyl]-6-(3-diethylamino-propoxy)- 1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 208

2-[5,7-bis-(2-pyrrolidin-1-yl-ethoxy)- 1H-benzimidazol-2-yl]-5-[2-(4-chloro- phenyl)-ethoxy]-phenol 209

2-[3-(4-tert-butyl-phenoxy)-phenyl]- 4,6-bis-(2-pyrrolodin-1-yl-ethoxy)- 1H-benzimidazole 210

(3-{6-(3-Diethylamino-propoxy)-2-[2- (1,1-difluoro-ethyl)-4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]- 1H-benzoimidazol-4-yloxy}-propyl)- diethyl-amine 211

{3-[1-Butyl-2-[4-(4-tert-butyl- phenoxy)-phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-yloxy]- propyl}-diethyl-amine 212

2-[4-(4-tert-Butyl-phenoxy)-phenyl]- 4,6-bis-(2-pyrrolidin-1-yl-ethoxy)- 1H-benzoimidazole 213

{3-[1-Butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-6-(2-pyrrolidin-1- yl-ethoxy)-1H-benzoimidazol-4- yloxy]-propyl}-diethyl-amine 214

[3-(3-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6- diethylaminomethyl-3H- benzimidazol-5-yloxy)-propyl]- diethyl-amine 215

(3-{6-(3-Diethylamino-propoxy)-2- [4-(4-fluoro-3-trifluoromethyl- phenoxy)-phenyl]-1H-benzoimidazol- 4-yloxy}-propyl)-diethyl-amine 216

(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[4-(4-trifluoromethyl- pyrimidin-2-ylsulfanyl)-phenyl]-1H- benzoimidazol-4-yloxy}-propyl)- diethyl-amine 217

{3-[6-(3-Diethylamino-propoxy)-2-(3- p-tolyloxy-phenyl)-1H-benzoimidazol- 4-yloxy]-propyl}-diethyl-amine 218

4-{3-[1-Butyl-4,6-bis-(3-diethylamino- propoxy)-1H-benzoimidazol-2-yl]- phenoxy}-benzonitrile 219

[3-(3-Butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-7-pyrrolidin-1-yl-3H- benzoimidazol-5-yloxy)-propyl]- diethyl-amine 220

{3-[1-butyl-2-[4-(4-chloro- phenylmethanesulfinyl)-phenyl]-6-(3- diethylamino-propoxy)-1H- benzimidazol-4-yloxy]-propyl}-diethyl- amine 221

(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[4-(naphthalen-2-yloxy)- phenyl]-1H-benzoimidazole-4-yloxy}- propyl)-diethyl-amine 222

(3-{6-(3-diethylamino-propoxy)-2-[4- (3-trifluoromethyl-phenoxy)-phenyl]- 1H-benzimidazol-4-yloxy}-propyl)- diethyl-amine 223

(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[3-(4-methoxy-phenoxy)- phenyl]-1H-benzimidazol-4-yloxy}- propyl)-diethyl-amine 224

2-[3-(3,4-Dichloro-phenoxy)-phenyl]- 4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 225

{3-[2-[4-(4-tert-Butyl-phenoxy)- phenyl]-6-(3-diethylamino-propoxy)- 1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 226

{3-[3-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-7-[2-(tetrahydro-furan- 2-yl)-ethoxy]-3H-benzimidazol-5-yloxy}- propyl)-diethyl-amine 227

1-Butyl-2-[4-(3-chloro-phenoxy)- phenyl]-4,6-bis-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazole 228

[3-(7-Butoxy-3-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-3H- benzoimidazol-5-yloxy)-propyl]- diethyl-amine 229

4-{3-[4,6-Bis-(3-diethylamino-propoxy)- 1H-benzoimidazol-2-yl]-phenoxy}- benzonitrile 230

2-[3-(3,5-Dichloro-phenoxy)-phenyl]- 4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 231

{3-[1-butyl-2-(2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-ethyl)-6-(3- diethylamino-propoxy)-1H- benzimidazol-4-yloxy]-propyl}-diethyl- amine 232

{3-[1-butyl-6-(3-diethylamino-propoxy)- 2-(3-phenoxy-phenyl)-1H-benzimidazol-4- yloxy]-propyl}-diethyl-amine 233

{3-[1-Butyl-2-[2-(4-chloro-3- trifluoromethyl-phenoxy)-phenyl]-6- (3-diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}- diethyl-amine 234

2-[4-(4-Chloro-3-trifluoromethyl- phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin- 1-yl-ethoxy)-1H-benzoimidazole 235

{3-[1-Butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]-6- (2-pyrrolidin-1-yl-ethoxy)-1H- benzoimidazol-4-yloxy]-propyl}- diethyl-amine 236

[3-(3-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-methyl-3H- benzimidazol-5-yloxy)-propyl]- diethyl-amine 237

{3-[1-butyl-6-(3-diethylamino- propoxy)-2-(4-phenoxy-phenyl)-1H- benzimidazol-4-yloxy]-propyl}- diethyl-amine 238

5-[4,6-bis-(3-diethylamino-propoxy)- 1H-benzoimidazlo-2-yl]-2-[2-(4- chloro-phenyl)-ethoxy]-phenol 239

[3-(6-Butoxy-1-butyl-2-{4-[2-(4- chloro-phenyl)-ethoxy]-phenyl}-1H- benzoimidazol-4-yloxy)-propyl]- diethyl-amine 240

{3-[2-[4-Chloro-2-(4-chloro-3- trifluoromethyl-phenoxy)-phenyl]-6- (3-diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}- diethyl-amine 241

1-butyl-4-(4-chloro-benzyloxy)-2-{4- [2-(4-chloro-phenyl)-ethoxy]- phenyl}-6-(2-pyrrolidin-1-yl-ethoxy)- 1H-benzimidazole 242

4-{4-[1-butyl-4,6-bis-(3-diethylamino- propoxy)-1H-benzimidazol-2-yl]- phenoxy}-benzonitrile 243

[3-(1-Butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-fluoro-1H- benzoimidazol-4-yloxy)-propyl]- diethyl-amine 244

(3-{6-(3-diethylamino-propoxy)-2-[3- (4-methoxy-phenoxy)-phenyl]-1H- benzimidazol-4-yloxy}-propyl)- diethyl-amine 245

(3-{6-(3-diethylamino-propoxy)-2-[4- (4-methoxy-phenoxy)-phenyl]-1H- benzimidazol-4-yloxy}-propyl)- diethyl-amine 246

{3-[1-butyl-2-[4-(4-chloro-3-fluoro- phenoxy)-phenyl]-6-(3-diethylamino- propoxy)-1H-benzimidazol-4-yl]- propyl}-diethyl-amine 247

(3-{1-butyl-6-(3-diethylamino-propoxy)- 2-[4-(quinolin-8-yloxy)-phenyl]-1H- benzimidazol-4-yloxy]-propyl}-diethyl- amine 248

{3-[2-[2-(4-chloro-3-trifluoromethyl- phenoxy)-phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4- yloxy]-propyl}-diethyl-ammne 249

2-[{2-[1-Butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy}-phenyl}-6-(2- morpholin-4-yl-ethoxy)-1H- benzoimidazol-4-yloxy]-ethyl}-(2- chloro-ethyl)-amino]-ethanol 250

(3-{6-(3-Diethylamino-propoxy)-2-[3- (4-fluoro-3-trifluoromethyl-phenoxy)- phenyl]-1H-benzoimidazol-4-yloxy}- propyl)-diethyl-amine 251

[3-(3-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-7-isopropoxy-3H- benzimidazol-5-yloxy)-propyl]- diethyl-amine 252

[3-(1-Butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-cyclopentylmethoxy- 1H-benzoimidazol-4-yloxy)-propyl]- diethyl-amine 253

1-Butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-4,6-bis-(2- morpholin-4-yl-ethoxy)-1H- benzoimidazole 254

{3-[2-[4-[2-(4-Chloro-phenyl)- ethoxy]-3-(3-diethylamino-propoxy)- phenyl]-6-(3-diethylamino-propoxy)- 1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 255

{3-[2-[1-butyl-6-(4-tert-butyl- phenoxy)-1H-benzimidazol-2-yl]-5- (3-diethylamino-propoxy)-phenoxy]- propyl}-diethyl-amine 256

(3-{2-[1-butyl-6-(3-diethylamino- propoxy)-1H-benzimidazol-2-yl]-5- [2-(4-chloro-phenyl)-ethoxy]-phenoxy}- propyl)-diethyl-amine 257

(3-{1-butyl-6-(4-tert-butyl-phenoxy)- 2-[4-(3-diethylamino-propoxy)- phenyl]-1H-benzoimidazol-4-yloxy}- propyl)-diethyl-amine 258

2-{2,4-bis-[2-(1-methyl-pyrrolidin-2- yl)-ethoxy]-phenyl}-1-butyl-6-(4-tert- butyl-phenoxy)-1H-benzoimidazole 259

2-[2,4-bis-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-1-butyl-6-(4-butyl-phenoxy)- 1H-benzoimidazole 260

1-butyl-2-[4-[2-(4-chloro-phenyl)- ethoxy]-2-(2-pyrrolodin-1-yl-ethoxy)- phenyl]-6-(2-pyrrolodin-1-yl-ethoxy)- 1H-benzoimidazole 261

{3-[2-{1-butyl-6-[2-(4-chloro-phenyl)- ethoxy]-1H-benzimidazol-2-yl]-5-(3- diethylamino-propoxy)-phenoxy]- propyl}-diethyl-amine 262

2-{2,4-bis-[2-(1-methyl-pyrrolidin-2- yl)-ethoxy]-phenyl}-1-butyl-6-(4-butyl- phenoxy)-1H-benzoimidazole 263

{3-[2-[1-butyl-5-(4-tert-butyl- phenoxy)-1H-benzimidazol-1-yl]-5- (3-diethylamino-propoxy)-phenoxy]- propyl}-diethyl-amine 264

1-Butyl-2-[3-(3,5-dichloro-phenoxy)- phenyl]-4,6-bis-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazole 265

2-[2,4-bis-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-1-butyl-6-(4-cyclopentyl- phenoxy)-1H-benzoimidazole 266

2-{2,4-bis-[2-(1-methyl-pyrrolidin-2-yl)- ethoxy}-phenyl}-1-butyl-6-(4-cyclopentyl- phenoxy)-1H-benzoimidazole 267

{3-[2-[1-butyl-6-(4-iospropyl- phenoxy)-1H-benzimidazol-2-yl]-5-(3- diethylamino-propoxy)-phenoxy]- propyl}-diethyl-amine 268

(2-{1-butyl-6-(2-dimethylamino- ethylsulfanyl)-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-2-(2- pyrrolidin-1-yl-ethoxy)-phenyl]-1H- benzoimidazol-4-ylsulfanyl}-ethyl)- dimethyl-amine 269

2-[2,4-bis-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-1-butyl-6-(4-tert-butyl- phenoxy)-1H-benzimidazole 270

{3-[2-[1-butyl-6-(4-butyl-phenoxy)-1H- benzimidazol-2-yl]-5-(3-diethylamino- propoxy)-phenoxy]-propyl}-diethyl- amine 271

{3-[2-[1-butyl-6-(4-fluoro-3- trifluoromethyl-phenoxy)-1H- benzimidazol-2-yl]-5-(3- diethylamino-propoxy)-phenoxy]-propyl}- diethyl-amine 272

2-[2,4-bis-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-1-butyl-6-(4-isopropyl- phenoxy)-1H-benzoimidazole 273

1-Butyl-2-[3-(3,4-dichloro-phenoxy)- phenyl]-4,6-bis-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazole 274

(3-{3-Butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-2-(2- pyrrolidin-1-yl-ethoxy)-phenyl]- 3H-benzoimidazol-5-yloxy}-propyl)- diethyl-amine 275

{3-[2-[1-butyl-6-(4-cyclopentyl- phenoxy)-1H-benzimidazol-2-yl]-5- (3-diethylamino-propoxy)-phenoxy]- propyl}-diethyl-amine 276

{3-[2-[1-butyl-4-(4-tert-butyl- phenoxy)-1H-benzimidazol-2-yl]-5- (3-diethylamino-propoxy)-phenoxy]- propyl}-diethyl-amine 277

2-{2,4-bis-[2-(1-methyl-pyrrolidin-2- yl)-ethoxy]-phenyl}-1-butyl-6-(4- isopropyl-phenoxy)-1H- benzoimidazole 278

(3-{5-[2-(4-chloro-phenyl)-ethoxy]-2- [6-(3-diethylamino-propoxy)-1- isopropyl-1H-benzimidazol-2-yl]- phenoxy}-propyl)-diethyl-amine 279

1-Butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-2-(2- pyrrolidin-1-yl-ethoxy)-phenyl]-6-(2- pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 280

1-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-4,6-bis-(1-methyl- piperidin-4-yloxy)-1H-benzimidazole 281

{3-[2-[6-(4-tert-butyl-phenoxy)-1H- benzimidazol-2-yl]-5-(3- diethylamino-propoxy)-phenoxy]- propyl}-diethyl-amine 282

1-butyl-2-[3-(3,4-dichloro-phenoxy)- phenyl]-4,6-bis-(1-methyl-pyrrolidin- 2-ylmethoxy)-1H-benzoimidazole 283

(3-{3-butyl-2-[4-[2-(4-chloro-phenyl)- ethoxy]-2-(2-diethylamino-ethoxy)- phenyl]-3H-benzimidazol-5-yloxy}- propyl)-diethyl-amine 284

(3-{2-[1-Butyl-6-(2-imidazol-1-yl- ethoxy)-1H-benzoimidazol-2-yl]-5- [2-(4-chloro-phenyl)-ethoxy]-phenoxy}- propyl)-diethyl-amine 285

(3-{2-[1-Butyl-6-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazol-2-yl]-5- [2-(4-chloro-phenyl)-ethoxy]- phenoxy}-propyl)-diethyl-amine 286

{3-[2-(3,5-bis-benzyloxy-phenyl)-3- butyl-3H-benzimidazol-5-yloxy]-propyl}- diethyl-amine 287

4,6-bis-(2-azepan-1-yl-ethoxy)-1-butyl- 2-[3-(4-tert-butyl-phenoxy)-phenyl]-1H- benzoimidazole 288

1-butyl-2-[3-(4-butyl-phenoxy)-phenyl]- 4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 289

1-butyl-2-[3-(4-tert-butyl-phenoxy)- phenyl]-4,6-bis-(1-methyl-pyrrolidin- 2-ylmethoxy)-1H-benzoimidazole 290

(2-{1-butyl-6-(2-dimethylamino- ethylsulfanyl)-2-[3-(3-trifluoromethyl- phenoxy)-phenyl]-1H-benzoimidazole-4- ylsufanyl}-ethyl)-dimethyl-amine 291

(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[4-(4-isopropyl- phenoxy)-phenyl]-1H-benzimidazol- 4-yloxy}-propyl)-diethyl-amine 292

4,6-bis-(2-azepan-1-yl-ethoxy)-1-butyl- 2-[3-(3,5-dichlorophenoxy)-phenyl]- 1H-benzoimidazole 293

1-butyl-2-[3-(4-tert-butyl-phenoxy)- phenyl]-4,6-bis-[2-(cyclohexyl- methyl-amino)-ethoxy]-1H- benzoimidazole 294

{3-[1-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-6-(2-imidazol-1- yl-ethoxy)-1H-benzimidazol-4-yloxy]- propyl}-diethyl-amine 295

[3-(2-{3,4-bis-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-3-butyl-3H- benzimidazol-5-yloxy)-propyl]- diethyl-amine 296

1-butyl-4,6-bis-(1-methyl-piperidin-4- yloxy)-2-[3-(3-trifluoromethyl- phenoxy)-phenyl]-1H-benzoimidazole 297

4,6-bis-(2-azepan-1-yl-ethoxy)-1- butyl-2-[3-(3-trifluoromethyl- phenoxy)-phenyl]-1H-benzoimidazole 298

1-butyl-2-[3-(3,4-dichloro-phenoxy)- phenyl]-4,6-bis-(1-ethyl-pyrrolidin-2- ylmethoxy)-1H-benzoimidazole 299

[3-(2-{2-benzyloxy-4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-3-butyl-3H- benzimidazol-5-yloxy]-propyl}- diethyl-amine 300

{3-[2-[1-Butyl-6-(3-diethylamino- propoxy)-1H-benzoimidazol-2-yl]-5- (4-fluoro-3-trifluoromethyl-phenoxy)- phenoxy]-propyl}-diethyl-amine 301

{3-[2-[1-Butyl-6-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazol-2-yl]-5- (4-fluoro-3-trifluoromethyl-phenoxy)- phenoxy]-propyl}-diethyl-amine 302

1-butyl-2-[3-(3,4-dimethoxy-phenoxy)- phenyl]-4,6-bis-(2-pyrrolidin-1- yl-ethoxy)-1H-benzimidazole 303

(2-{1-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-(2-dimethylamino- ethylsulfanyl)-1H-benzoimidazol-4- ylsulfanyl}-ethyl)-dimethyl-amine 304

1-butyl-2-[3-(4-tert-butyl-phenoxy)- phenyl]-4,6-bis-(1-ethyl-pyrrolidin-3- yloxy)-1H-benzoimidazole 305

{3-[2-[3-(3,4-bis-benzyloxy-phenyl)- 3-butyl-3H-benzimidazol-5-yloxy]- propyl}-diethyl-amine 306

(3-{5-[2-(4-chloro-phenyl)-ethoxy]-2- [6-(3-diethylamino-propoxy)-1H- benzimidazol-2-yl]-phenoxy}-propyl)- diethyl-amine 307

1-butyl-2-[4-(2-diethylamino-ethoxy)- phenyl]-4,6-bis-[2-(methyl-phenyl- amino)-ethoxy]-1H-benzimidazole 308

{3-[3-butyl-2-{4-[2-(4-chlorophenyl)- ethoxy]-phenyl}-7-(pyridin-3-yloxy)- 3H-benzimidazol-5-yloxy]-propyl}- diethyl-amine 309

{2-[1-butyl-2-[3-(3,4-dichloro-phenoxy)- phenyl]-6-(2-diisopropylamino-ethoxy)- 1H-benzimidazol-4-yloxy]-ethyl}- diethyl-amine 310

{3-[3-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-7-(pyridin-3- ylmethoxy)-3H-benzimidazol-5- yloxy]-propyl}-diethyl-amine 311

2-[1-butyl-6-(3-diethylamino- propoxy)-1H-benzoimidazlo-2-yl]-5- [2-(4-chloro-phenyl)-ethoxy]-phenol 312

{3-[3-butyl-2-[2-(4-chloro- phenylsulfanyl)-phenyl]-7-(3- diethylamino-propoxy)-3H- benzimidazol-4-yloxy}-propyl)-diethyl- amine 313

(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[4-(4-fluoro-2-methoxy- phenoxy)-phenyl]-1H-benzimidazol- 4-yloxy}-propyl)-diethyl-amine 314

[3-(3-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-2-isopropoxy-phenyl}-3H- benzimidazol-5-yloxy)-propyl]- diethyl-amine 315

{2-[1-butyl-6-(3-diethylamino- propoxy)-1H-benzoimidazol-2-yl]-5- [2-(4-chloro-phenyl)-ethoxy]- phenoxy}-acetic acid methyl ester 316

(3-{2-[1-butyl-6-(4-tert-butyl- phenoxy)-1H-benzimidazol-2-yl]-5- [2-(4-chloro-phenyl)-ethoxy]- phenoxy}-propyl)-diethyl-amine 317

(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[4-(2-isopropoxy- phenoxy)-phenyl]-1H-benzoimidazol- 4-yloxy}-propyl)-diethyl-amine 318

(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[4-(2,3-dimethoxy- phenoxy)-phenyl]-1H-benzimidazol- 4-yloxy}-propyl)-diethyl-amine 319

(3-{3-Butyl-2-[4-[2-(4-chloro-phenyl)- ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-3H-benzoimidazol-5-yloxy}- propyl)-diethyl-amine 320

(2-{1-butyl-6-fluoro-2-[3-(3- trifluoromethyl-phenoxy)-phenyl]-1H- benzoimidazole-4-ylsufanyl}-ethyl)- dimethyl-amine 321

Methanesulfonic acid 5-[2-(4-chloro- phenyl)-ethoxy]-2-[6-(3-diethylamino- propoxy)-1H-benzoimidazol- 2-yl]-phenyl ester 322

5-[2-(4-Chloro-phenyl)-ethoxy]-2-[6- (3-diethylamino-propoxy)-1H- benzoimidazol-2-yl]-phenol 323

{3-[1-butyl-6-(3-diethylamino-propoxy)- 2-(4-pyrrolidin-1-yl-phenyl)-1H- benzoimidazol-4-yloxy]-propyl}-diethyl- amine 324

1-butyl-2-[3-(4-tert-butyl-phenoxy)- phenyl]-4,6-bis-(1-methyl-piperidin- 4-yloxy)-1H-benzimidazole 325

1-butyl-2-[3-(3,5-dichloro-phenoxy)- phenyl}-4,6-bis-(2-imidazol-1-yl- ethoxy)-1H-benzoimidazole 326

[2-(1-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-fluoro-1H- benzoimidazol-4-ylsulfanyl)-ethyl]- dimethyl-amine 327

{3-[1-Butyl-2-[4-[2-(4-chloro-phenyl)- ethoxy]-2-(2-(pyrrolidin-1-yl-ethoxy)- phenyl]-6-(3-diethylamino-propoxy)- 1H-benzimidazol-4-yloxy]-propyl}- diethyl-amine 328

1-Butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-2-(2- pyrrolidin-1-yl-ethoxy)-phenyl]-4,6-bis- (2-pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 329

1-Butyl-2-[4-(4-chloro-3- trifluoromethyl-phenoxy)-2-(2- pyrrolidin-1-yl-ethoxy)-phenyl]-4,6-bis- (2-pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 330

(3-{2-[1-butyl-6-(3-diethylamino- propoxy)-4-(2-pyrrolidin-1-yl-ethoxy)- 1H-benzimidazol-2-yl]-5-[2-(4-chloro- phenyl)-ethoxy]-phenoxy}-propyl)- diethyl-amine 331

(3-{2-[1-butyl-4,6-bis-(3-diethylamino- propoxy)-1H-benzimidazol-2-yl]-5- [2-(4-chloro-phenyl)-ethoxy]- phenoxy}-propyl)-diethyl-amine 332

(3-{2-[1-Butyl-4,6-bis-(2-pyrrolidin-1- yl-ethoxy)-1H-benzoimidazol-2-yl]-5- [2-(4-chloro-phenyl)-ethoxy]- phenoxy}-propyl)-diethyl-amine 333

(3-{1-Butyl-6-(3-diethylamino-propoxy)- 2-[4-(4-fluoro-3-trifluoromethyl- phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-1H-benzoimidazol-4- yloxy}-propyl)-diethyl-amine 334

{3-[1-Butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-2-(2- pyrrolidin-1-yl-ethoxy)-phenyl]-6-(2- pyrrolidin-1-yl-ethoxy)-1H- benzoimidazol-4-yloxy]-propyl}- diethyl-amine 335

{3-[2-[1-Butyl-6-(3-diethylamino- propoxy)-4-(2-pyrrolidin-1-yl-ethoxy)- 1H-benzoimidazol-2-yl]-5-(4-fluoro-3- trifluoromethyl-phenoxy)-phenoxy]- propyl}-diethyl-amine 336

{3-[2-[1-Butyl-4,6-bis-(2-pyrrolidin-1- yl-ethoxy)-1H-benzoimidazol-2-yl]-5- (4-fluoro-3-trifluoromethyl-phenoxy)- phenoxy]-propyl}-diethyl-amine 337

{3-[3-butyl-2-[4-[2-(4-chloro-phenyl)- ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-7-(2-pyrrolidin-1-yl-ethoxy)- 3H-benzimidazol-5-yloxy]-propyl}- diethyl-amine 338

(3-{2-[1-Butyl-4-(3-diethylamino- propoxy)-6-(2-pyrrolidin-1-yl-ethoxy)- 1H-benzoimidazol-2-yl]-5-[2-(4- chloro-phenyl)-ethoxy]-phenoxy}- propyl)-diethyl-amine 339

{3-[1-butyl-2-[4-(3,4-dichloro- phenoxy)-2-(2-pyrrolidin-1-yl- ethoxy)-phenyl]-6-(3-diethylamino- propoxy)-1H-benzimidazol-4-yloxy]- propyl}-diethyl-amine 340

{3-[2-[2,4-bis-(3-diethylamino- propoxy)-phenyl]-1-butyl-6-(4-tert- butyl-phenoxy)-1H-benzoimidazol- 4-yloxy]-propyl}-diethyl-amine 341

{3-[1-butyl-2-[4-[2-(4-chloro-phenyl)- ethoxy]-2-(pyridin-2-ylmethoxy)- phenyl]-6-(3-diethylamino-propoxy)- 1H-benzimidazol-4-yl]-phenyl}- diethyl-amine 342

{3-[2-[4-[2-(4-Chloro-phenyl)-ethoxy] -2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]- 6-(3-diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}- diethyl-amine 343

1-Butyl-2-[4-[2-(4-chloro-phenyl)- ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-4,6-bis-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazole 344

{3-[1-Butyl-2-[4-(4-chloro-3- trifluoromethyl-phenoxy)-2-(2- pyrrolidin-1-yl-ethoxy)-phenyl]- 6-(3-diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}- diethyl-amine 345

(3-{6-(3-Diethylamino-propoxy)-2-[4- (4-fluoro-3-trifluoromethyl-phenoxy)- 2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]- 1H-benzoimidazol-4-yloxy}-propyl)- diethyl-amine 346

{3-[2-[1-Butyl-4-(3-diethylamino- propoxy)-6-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazol-2-yl]-5- (4-fluoro-3-trifluoromethyl-phenoxy)- phenoxy]-propyl}-diethyl-amine 347

{3-[3-Butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-2-(2- pyrrolidin-1-yl-ethoxy)-phenyl]-7-(2- pyrrolidin-1-yl-ethoxy)-3H- benzoimidazol-5-yloxy]-propyl}- diethyl-amine 348

{3-[1-butyl-2-[4-[2-(4-chloro-phenyl)- ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-6-(2-pyrrolidin-1-yl-ethoxy)- 1H-benzimidazol-4-yloxy]-propyl}- diethyl-amine 349

{3-[2-[1-butyl-4,6-bis-(2-pyrrolodin-1- yl-ethoxy)-1H-benzimidazol-2-yl]-5- (4-fluoro-3-trifluoromethyl-phenoxy)- phenyl]-propyl}-diethyl-amine 350

{3-[1-butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-3-diethylaminomethyl- phenyl}-6-(3-diethylamino-propoxy)- 1H-benzimidazol-4-yloxy]-propyl}- diethyl-amine 351

{3-[2-[4-[2-(4-chloro-phenyl)-ethoxy]- 2-(pyridin-2-ylmethoxy)-phenyl]-6- (3-diethylamino-propoxy)-1H- benzimidazol-4-yl]-propyl}- diethyl-amine 352

3-(7-Butoxy-3-butyl-2-{4-[2-(4- chloro-phenyl)-ethoxy]-2- cyclopentylmethoxy-phenyl}-3H- benzoimidazol-5-yloxy)-propan-1-ol 353

3-(7-Butoxy-2-{4-[2-(4-chloro-phenyl)- ethoxy]-2-cyclopentyl-methoxy-phenyl}- 3H-benzoimidazol-5-yloxy)-propan-1-ol 354

(3-{1-Butyl-6-(3-diethylamino- propoxy)-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-2-(pyridin- 2-ylmethoxy)-phenyl]-1H- benzoimidazol-4-yloxy}-propyl)- diethyl-amine 355

{3-[2-[1-Butyl-4,6-bis-(3- diethylamino-propoxy)-1H- benzoimidazol-2-yl]-5-(4-fluoro-3- trifluoromethyl-phenoxy)-phenoxy]- propyl}-diethyl-amine 356

2-(3,5-bis-benzyloxy-phenyl)-1-butyl- 4,6-bis-(2-pyrrolodin-1-yl-ethoxy)-1H- benzimidazole 357

{3-[2-[1-butyl-4,6-bis-(3- diethylamino-propoxy)-1H- benzimidazol-2-yl]-5-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]- propyl}-diethyl-amine 358

1-butyl-2-[4-[2-(4-chloro-phenyl)- ethoxy]-2-(2-pyrrol-1-yl-ethoxy)-phenyl]- 4,6-bis-(2-pyrrolodin-1-yl-ethoxy)- 1H-benzoimidazole 359

{3-[2-{4-[2-(4-chloro-phenyl)- ethoxy]-2-(3-diethylamino-propoxy)- phenyl}-6-(3-diethylamino-propoxy)- 1H-benzimidazol-4-yloxy]-propyl}- diethyl-amine 360

{3-[1-Butyl-2-[4-[2-(4-chloro-phenyl)- ethoxy]-2-(pyridin-3-ylmethoxy)- phenyl]-6-(3-diethylamino-propoxy)- 1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 361

(3-{3-Butyl-2-[4-[2-(4-chloro-phenyl)- ethoxy]-2-(3-diethylamino-propoxy)- phenyl]-7-isopropoxy-3H- benzoimidazol-5-yloxy}-propyl)- diethyl-amine 362

{3-[1-Butyl-2-[4-[2-(4-chloro-phenyl)- ethoxy]-2-(pyridin-4-ylmethoxy)- phenyl]-6-(3-diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}- diethyl-amine 363

{3-[2-[4-[2-(4-Chloro-phenyl)- ethoxy]-2-(pyridin-4-ylmethoxy)- phenyl]-6-(3-diethylamino-propoxy)- 1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 364

1-Butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-2-(pyridin- 2-ylmethoxy)-phenyl]-4,6-bis-(2- pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 365 cor- rect

2-[4-[2-(4-chloro-phenyl)-ethoxy]-2- (2-pyrrolidin-1-yl-ethoxy)-phenyl]- 5,7-bis-(2-pyrrolidin-1-yl-ethoxy)- 1H-benzimidazole 366

{3-[1-Butyl-2-{4-[2-(4-chloro-phenyl)- ethoxy]-2-methoxy-phenyl}-6-(3- diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}- diethyl-amine 367

{3-[2-{4-[2-(4-Chloro-phenyl)- ethoxy]-2-methoxy-phenyl}-6-(3- diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}- diethyl-amine 368

(3-{1-Butyl-2-[4-[2-(4-chloro-phenyl)- ethoxy]-2-(3-diethylamino-propoxy)- phenyl]-6-isopropoxy-1H-benzoimidazol- 4-yloxy}-propyl)-diethyl-amine 369

{3-[1-Butyl-2-[4-(4-chloro-3-methyl- phenoxy)-2-(pyridin-2-ylmethoxy)- phenyl]-6-(3-diethylamino-propoxy)- 1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 370

1-Butyl-2-[4-(4-chloro-3- trifluoromethyl-phenoxy)-2- cyclopentylmethoxy-phenyl]-4,6-bis- (2-pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 371

(2-{1-butyl-6-(2-dimethylamino- ethoxy)-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-2-(2- pyrrolidin-1-yl-ethoxy)-phenyl]-1H- benzoimidazole-4-yloxy}-ethyl)- dimethyl-amine 372

2-[1-butyl-4,6-bis-(3-diethylamino- propoxy)-1H-benzimidazol-2-yl]-5- [2-(4-chloro-phenyl)-ethoxy]-phenol 373

1-Butyl-2-[4-(4-chloro-3-methyl- phenoxy)-2-(pyridin-2-ylmethoxy)- phenyl]-4,6-bis-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazole 374

2-[4-(4-Chloro-3-trifluoromethyl- phenoxy)-2-cyclopentylmethoxy- phenyl]-4,6-bis-(2-pyrrolidin-1- yl-ethoxy)-1H-benzoimidazole 375

2-[4-(4-Fluoro-3-trifluoromethyl- phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-4,6-bis-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazole 376

{3-[2-(3,5-bis-benzyloxy-phenyl)-1- butyl-6-(3-diethylamino-propoxy)- 1H-benzimidazol-4-yloxy]-propyl}- diethyl-amine 377

(3-{1-butyl-6-(3-dimethylamino- propoxy)-2-[4-(3-fluoro-phenoxy)-2- (2-pyrrolidin-1-yl-ethoxy)-phenyl]- 1H-benzoimidazole-4-yloxy}-propyl)- diethyl-amine 378

{3-[2-{1-butyl-4-(4-chloro- benzyloxy)-6-(2-pyrrolidin-1-yl- ethoxy)-1H-benzimidazol-2-yl]-5-[2- (4-chloro-phenyl)-ethoxy]-phenoxy}- propyl)-diethyl-amine 379

{3-[2-{4-[2-(4-chloro-phenyl)- ethoxy]-2-(3-diethylamino-propoxy)- phenyl]-6-(3-diethylamino-propoxy)- 3H-benzimidazol-4-yloxy]-propyl}- diethyl-amine 380

{3-[2-[4-(3,4-dichloro-phenoxy)-2-(2- pyrrolidin-1-yl-ethoxy)-phenyl]-6-(3- diethylamino-propoxy)-1H- benzimidazol-4-yloxy]-propyl}- diethyl-amine 381

{3-[1-Butyl-2-[4-(4-chloro-3- trifluoromethyl-phenoxy)-2- cyclopentylmethoxy-phenyl]-6-(3- diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}-diethyl- amine 382

{3-[2-[4-(4-chloro-3-trifluoromethyl- phenoxy)-2-cyclopentylmethoxy- phenyl]-6-(3-diethylamino-propoxy)- 1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 383

(3-{1-butyl-6-(4-tert-butyl-phenoxy)- 2-[4-[2-(4-chloro-phenyl)-ethoxy]-2- (3-diethylamino-propoxy)-phenyl]- 1H-benzimidazol-4-yloxy}-propyl)- diethyl-amine 384

2-{2,4-bis-[2-(4-chloro-phenyl)-ethoxy]- phenyl}-1-butyl-4,6-bis-(2-pyrrolidin-1- yl-ethoxy)-1H-benzimidazole 385

(2-{1-butyl-6-(2-dimethylamino- ethoxy)-2-[4-(3-fluoro-phenoxy)-2- (2-pyrrolidin-1-yl-ethoxy)-phenyl]- 1H-benzoimidazole-4-yloxy}-ethyl)- dimethyl-amine 386

{3-[2-[4-(3,5-bis-trifluoromethyl- phenoxy)-2-(2-pyrrolidin-1-yl- ethoxy)-phenyl]-1-butyl-6-(3- diethylamino-propoxy)-1H- benzimidazol-4-yloxy]-propyl}- diethyl-amine 387

{3-[1-butyl-2-[4-[2-(4-chloro-phenyl)- ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-6-(3-diethylamino-propoxy)- 1H-benzimidazol-4-yloxy]-propyl}- diethyl-amine 388

(3-{2-(1-Butyl-4,6-diisopropoxy-1H- benzoimidazol-2-yl)-5-[2-(4-chloro- phenyl)-ethoxy]-phenoxy}-propyl)- diethyl-amine 389

{3-[1-butyl-2-{3-[2-(4-chloro-phenyl)- ethoxy]-4-diethylaminomethyl- phenyl}-6-(3-diethylamino-propoxy)- 1H-benzimidazol-4-yloxy]-propyl}- diethyl-amine 390

(3-{1-Butyl-6-(3-diethylamino- propoxy)-2-[4-fluoro-2-(2-pyrrolidin- 1-yl-ethoxy)-phenyl]-1H-benzoimidazol- 4-yloxy}-propyl)-diethyl-amine 391

(2-{1-butyl-6-fluoro-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-2-(2- pyrrolidin-1-yl-ethoxy)-phenyl]-1H- benzoimidazol-4-ylsulfanyl}-ethyl)- dimethyl-amine 392

{3-[1-Butyl-2-[4-[2-(4-chloro-phenyl)- ethoxy]-3-(3-diethylamino-propoxy)- phenyl]-6-(3-diethylamino-propoxy)- 1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 393

(4-benzyloxy-benzyl)-[1-butyl-6-(3- diethylamino-propoxy)-1H- benzimidazol-2-ylmethyl]-hexyl-amine 394

(4-benzyloxy-benzyl)-[1-butyl-6-(3- diethylamino-propoxy)-1H- benzimidazol-2-ylmethyl]-isobutyl- amine 395

[3-(2-{[(4-benzyloxy-benzyl)- cyclopentylmethyl-amino]-methyl}-3- butyl-3H-benzimidazol-5-yloxy)- propyl]-diethyl-amine 396

N-(4-benzyloxy-benzyl)-N-[1-butyl- 6-(3-diethylamino-propoxy)-1H- benzimidazol-2-ylmethyl]-benzamide 397

(3-{3-butyl-2-[(dibenzylamino)- methyl]-3H-benzimidazol-5-yloxy)- propyl]-diethyl-amine 398

(3-{2-[(4-benzyloxy-benzylamino)- methyl]-3-butyl-3H-benzimidazol-5- yloxy}-propyl)-diethyl-amine 399

N-(4-benzyloxy-benzyl)-N-[1-butyl-6- (3-diethylamino-propoxy)-1H- benzimidazol-2-ylmethyl]- methanesulfonamide 400

N-(4-benzyloxy-benzyl)-N-[1-butyl-6- (3-diethylamino-propoxy)-1H- benzimidazol-2-ylmethyl]-acetamide 401

{3-[3-butyl-2-({4-[2-(4-chloro- phenyl)-ethoxy]-benzylamino}- methyl)-3H-benzimidazol-5-yloxy)- propyl]-diethyl-amine 402

[3-(2-{[Bis-(4-benzyloxy-benzyl)- amino]-methyl}-3-butyl-3H- benzoimidazol-5-yloxy)- propyl]-diethyl-amine 403

[3-(2-{[Benzyl-(4-benzyloxy- benzyl)-amino]-methyl}-3-butyl-3H- benzoimidazol-5-yloxy)-propyl]- diethyl-amine 404

{3-[4-(2-butyl-4-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-imidazol-1- yl)-phenoxy]-propyl}-diethyl-amine 405

{3-[4-(4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-isobutyl-imidazol- 1-yl)-phenoxy]-propyl}-diethyl-amine 406

[3-(4-{2-butyl-1-[4-(4-chloro- phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-propyl}-diethyl-amine 407

1-[4-(4-{2-butyl-1-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]- 1H-imidazol-4-yl}-phenoxy)-butyl]- piperazine 408

4-(4-{2-butyl-1-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]- 1H-imidazol-4-yl}-phenoxy)-1- methyl-piperidine 409

1-[5-(4-{2-butyl-1-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]- 1H-imidazol-4-yl}-phenoxy)-pentyl]- piperazine 410

{3-[4-(4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-imidazol-1-yl)- phenoxy]-propyl}-diethyl-amine 411

{3-[3-(4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-imidazol-1-yl)- phenoxy]-propyl}-diethyl-amine 412

[3-(4-{1-[4-(4-tert-butyl-phenoxy)- phenyl]-1H-imidazol-4-yl)-phenoxy)- propyl]-diethyl-amine 413

[3-(4-{2-butyl-1-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]- 1H-imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 414

diethyl-[3-(4-{1-[4-(4- trifluoromethoxy-phenoxy)-phenyl]-1H- imidazol-4-yl}-phenoxy)-propyl]- amine 415

[3-(4-{2-butyl-1-[4-(3,4-dichloro- phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-propyl]-diethyl-amine 416

[3-(4-{2-cyclobutyl-1-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]- 1H-imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 417

[3-(4-{2-cyclopentyl-1-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]- 1H-imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 418

[3-(4-{2-cyclohexyl-1-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]- 1H-imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine. 419

diethyl-[3-(4-{1-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]-2- isobutyl-1H-imidazol-4-yl}- phenoxy)-propyl]-amine 420

[3-(4-{2-but-3-enyl-1-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]- 1H-imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 421

[3-(4-{2-tert-butyl-1-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]- 1H-imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 422

diethyl-[3-(4-{2-(4-fluoro-phenyl)-1- [4-(4-fluoro-3-trifluoromethyl- phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-propyl]-amine 423

[3-(4-{1-[4-(3,5-bis-trifluoromethyl- phenoxy)-phenyl]-2-butyl-1H- imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 424

(3-{4-[1-(4-benzyloxy-phenyl)-2- butyl-1H-imidazol-4-yl]-phenoxy}- propyl)-diethyl-amine 425

{3-[4-(2-tert-butyl-4-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-imidazol-1- yl)-phenoxy]-propyl}-diethyl-amine 426

[3-(4-{2-butyl-1-[4-(3-fluoro-4- trifluoromethyl-phenoxy)-phenyl]- 1H-imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 427

diethyl-[3-(4-{4-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]- imidazol-1-yl}-phenoxy)-propyl]-amine 428

(3-{4-[4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-(4-fluoro-phenyl)- imidazol-1-yl]-phenoxy}-propyl)- diethyl-amine 429

{3-[4-(4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-cyclopropyl- imidazol-1-yl)-phenoxy]-propyl}- diethyl-amine 430

{3-[4-(4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-cyclopentyl- imidazol-1-yl)-phenoxy]-propyl}- diethyl-amine 431

[3-(4-{4-[4-(biphenyl-4-yloxy)- phenyl]-imidazol-1-yl}-phenoxy)- propyl]-diethyl-amine 432

diethyl-[3-(4-{4-[4-(3-trifluoromethyl- phenoxy)-phenyl]-imidazol-1-yl}- phenoxy)-propyl]-amine 433

[3-(4-{4-[4-(3,4-dichloro-phenoxy)- phenyl]-imidazol-1-yl}-phenoxy)- propyl]-diethyl-amine 434

[3-(4-{2-butyl-1-[4-(4-methoxy- phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-propyl]-diethyl-amine 435

1-[2-(4-{2-butyl-1-[4-(3-fluoro-4- trifluoromethyl-phenoxy)-phenyl]- 1H-imidazol-4-yl}-phenoxy)-ethyl]- piperazine 436

{3-[4-(4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-imidazol-1-yl)- phenoxy]-propyl}-dimethyl-amine 437

4-{4-[2-(4-chloro-phenyl)-ethoxy]- phenyl}-1-{4-[2-(1-methyl-pyrrolidin- 2-yl)-ethoxy]-phenyl}-1H-imidazole 438

1-{2-[4-(4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-imidazol-1-yl)- phenoxy]-ethyl}-piperazine 439

[3-(4-{2-(3-cyclohexyl-propyl)-1-[4- (4-fluoro-3-trifluoromethyl-phenoxy)- phenyl]-1H-imidazol-4-yl}-phenoxy)- propyl]-diethyl-amine 440

diethyl-(3-{4-[1-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]-2- (3-phenoxy-propyl)-1H-imidazol-4- yl]-phenoxy}-propyl)-amine 441

{3-[4-(4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-methyl-imidazol- 1-yl)-phenoxy]-propyl}-diethyl-amine 442

3-(4-{2-butyl-1-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]- 1H-imidazol-4-yl}-phenoxy)-1-ethyl- piperidine 443

diethyl-[3-(4-{1-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]-2- methyl-1H-imidazol-4-yl}-phenoxy)- propyl]-amine 444

(3-{4-[4-(4-benzyloxy-phenyl)-2-butyl- imidazol-1-yl]-phenoxy}-propyl)- diethyl-amine 445

[3-(4-{2-butyl-1-[4-(2,5-difluoro- benzyloxy)-phenyl]-1H-imidazol-4- yl}-phenoxy)-propyl]-diethyl-amine 446

3-(S)-(4-{2-butyl-1-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]- 1H-imidazol-4-yl}-phenoxymethyl)-1- ethyl-piperidine 447

(3-{4-[4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-(2,4,4-trimethyl- pentyl)-imidazol-1-yl]-phenoxy}- propyl)-diethyl-amine 448

3-(R)-(4-{2-butyl-1-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]- 1H-imidazol-4-yl}-phenoxymethyl)-1- ethyl-piperidine 449

[3-(4-{2-butyl-1-[4-(3-tert-butyl- phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-propyl]-diethyl-amine 450

{3-[4-(4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-methoxymethyl- imidazol-1-yl)-phenoxy]-propyl}- diethyl-amine 451

(3-{4-[4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-(1-ethyl-propyl)- imidazol-1-yl]-phenoxy}-propyl)- diethyl-amine 452

(3-{4-[4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-(3-phenoxy-propyl)- imidazol-1-yl]-phenoxy}-propyl)- diethyl-amine 453

(3-{4-[4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-(1-propyl-butyl)- imidazol-1-yl]-phenoxy}-propyl)- diethyl-amine 454

{3-[4-(2-(4-chloro-phenoxymethyl)-4- {4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}- imidazol-1-yl)-phenoxy]-propyl}- diethyl-amine 455

{3-[4-(2-benzyloxymethyl-4-{4-[2-(4- chloro-phenyl)-ethoxy}-phenyl}- imidazol-1-yl)-phenoxy]-propyl}- diethyl-amine 456

{3-[4-(4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-isobutyl-5-methyl- imidazol-1-yl)-phenoxy]-propyl}- diethyl-amine 457

{3-[4-(4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-isobutyl-5-propyl- imidazol-1-yl)-phenoxy]-propyl}- diethyl-amine 458

{3-[4-(5-butyl-4-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-2-isobutyl- imidazol-1-yl)-phenoxy]-propyl}- diethyl-amine 459

{4-{4-{2-(4-chloro-phenyl)-ethoxy]- phenyl}-1-[4-(3-diethylamino- propoxy)-phenyl]-1H-imidazol-2-yl}- MeOH 460

diethyl-[3-(4-{2-isobutyl-4-[4-(4- phenoxy-benzyloxy)-phenyl]-imidazol- 1-yl}-phenoxy)-propyl]-amine 461

[3-(4-{4-[4-(4-benzyloxy-benzyloxy)- phenyl]-2-isobutyl-imidazol-1-yl}- phenoxy)-propyl]-diethyl-amine 462

[3-(4-{4-[4-(2-benzenesulfonylmethyl- benzyloxy)-phenyl]-2-isobutyl- imidazol-1-yl}-phenoxy)-propyl]- diethyl-amine 463

diethyl-[3-(4-{2-isobutyl-4-[4-(3,4,5- trimethoxy-benzyloxy)-phenyl]- imidazol-1-yl}-phenoxy)-propyl]- amine 464

[3-(4-{1-[4-(4-chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}- phenoxy)-propyl]-diethyl-amine 465

[3-(4-{1-[4-(4-chloro-phenoxy)- phenyl]-2-(2-cyclopentyl-ethyl)- 1H-imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 466

[3-(4-{1-[4-(4-chloro-phenoxy)- phenyl]-2-phenethyl-1H-imidazol-4- yl}-phenoxy)-propyl]-diethyl-amine 467

[3-(4-{2-(4-tert-butyl-phenoxymethyl)- 1-[4-(4-chloro-phenoxy)-phenyl]-1H- imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 468

[3-(4-{2-butyl-1-[4-(2,4-dichloro- phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-propyl]-diethyl-amine 469

[3-(4-{2-butyl-1-[4-(4-chloro- phenoxy)-phenyl]-5-methyl-1H- imidazol-4-yl)-phenoxy)-propyl]- diethyl-amine 470

[3-(4-{2-butyl-1-[4-(4-chloro- phenoxy)-phenyl]-5-propyl-1H- imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 471

[3-(4-{2,5-dibutyl-1-[4-(4-choro- phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-propyl]-diethyl-amine 472

[3-(4-{2-butyl-1-[4-(4-chloro- phenoxy)-phenyl]-5-ethyl-1H- imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 473

2-butyl-1-[4-(4-chloro-phenoxy)- phenyl]-4-[4-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-1H-imidazole 474

1-[2-(4-{2-butyl-1-[4-(4-chloro- phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-ethyl]-piperidine 475

[3-(4-{2-butyl-1-[4-(4-chloro- phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-2,2-dimethyl-propyl]- dimethyl-amine 476

[2-(4-{2-butyl-1-[4-(4-chloro- phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-ethyl]-diisopropyl-amine 477

[3-(4-{4-[4-(adamantan-1-ylmethoxy)- phenyl]-2-isobutyl-imidazol-1-yl}- phenoxy)-propyl]diethyl-amine 478

{3-[4-(4-{4-[3-(2,6-dichloro-phenyl)- 4-methyl-isoxazol-5-ylmethyloxy]- phenyl}-2-isobutyl-imidazol-1-yl)- phenoxy]-propyl}-diethyl-amine 479

[3-(4-{4-[4-(4-bromo-benzyloxy)- phenyl]-2-isobutyl-imidazol-1-yl}- phenoxy)-propyl]-diethyl-amine 480

[3-(4-{2-butyl-1-[4-(6-methoxy- naphthalen-2-yloxy)-phenyl]-1H- imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 481

[3-(4-{2-butyl-1-[4-(naphthalen-2- yloxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-propyl]-diethyl-amine 482

[3-(4-{2-butyl-1-[4-(4-methoxy- naphthalen-1-yloxy)-phenyl]-1H- imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 483

[3-(4-{2-butyl-1-[4-(dibenzofuran-2- yloxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-propyl]-diethyl-amine 484

6-(4-{2-butyl-4-[4-(3-diethylamino- propoxy)-phenyl]-imidazol-1-yl}- phenoxy)-naphthalen-2-ol 485

[3-(4-{2-butyl-4-[4-(4-chloro- phenoxy)-phenyl]-imidazol-1-yl}- phenoxy)-propyl]-diethyl-amine 486

[3-(4-{2-(4-tert-butyl-cyclohexyl)-1- [4-(4-chloro-phenoxy)-phenyl]-1H- imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 487

[3-{4-[1-[4-(4-chloro-phenoxy)- phenyl]-2-(trans-4-ethyl-cyclohexyl)- 1H-imidazol-4-yl]-phenoxy}-propyl)- diethyl-amine 488

[4-(4-{2-butyl-1-[4-(4-chloro- phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-phenyl}-(1-ethyl-piperidin- 4-ylmethyl)-amine 489

[4-{1-[4-(4-chloro-phenoxy)-phenyl]- 4-[4-(3-diethylaminopropoxy)- phenyl]-1H-imidazol-2-yl}-butyric acid methyl ester 490

[3-(4-{2-butyl-1-[4-(4-chloro-2- cyclohexyl-phenoxy)-phenyl]-1H- imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 491

[3-(4-{1-[4-(biphenyl-4-yloxy)- phenyl]-2-butyl-1H-imidazol-4-yl}- phenoxy)-propyl]-diethyl-amine 492

[3-(4-{1-[4-(4-bromo-phenoxy)- phenyl]-2-butyl-1H-imidazol-4-yl}- phenoxy)-propyl]-diethyl-amine 493

N-[4-(4-{2-butyl-4-[4-(3- diethylamino-porpoxy)-phenyl]- imidazol-1-yl}-phenoxy)-phenyl]- acetamide 494

(3-{4-[2-butyl-1-(4-p-tolyloxy- phenyl)-1H-imidazol-4-yl]- phenoxy}-propyl)-diethyl-amine 495

[3-(4-{2-butyl-1-[4-(4-fluoro- phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-propyl]-diethyl-amine 496

[3-(4-{2-butyl-1-[4-(4-chloro-3-ethyl- phenoxy)-phenyl]-1H-imidazol-4-yl}- phenoxy)-propyl]-diethyl-amine 497

{2-[4-(2-butyl-4-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-imidazol-1- yl)-phenoxy]-ethyl}-ethyl-amine 498

[3-(4-{5-butyl-4-[4-(3,3-diphenyl- propoxy)-phenyl]-2-isobutyl-1H- imidazol-4-yl}-phenoxy)-2,2- dimethyl-propyl]-dimethyl-amine 499

[3-(4-{4-[4-(3,3-diphenyl-propoxy)- phenyl]-2-isobutyl-imidazol-1-yl}- phenoxy)-propyl]-diethyl-amine 500

7-{2-butyl-4-[4-(4-chloro-phenoxy)- naphthalen-1-yl]-imidazol-1-yl}- 1,2,3,4-tetrahydro-isoquinoline 501

2-biphenyl-4-yl-N-{4-[2-butyl-1- (1,2,3,4-tetrahydro-isoquinolin-7-yl)- 1H-imidazol-4-yl]-phenyl}-acetamide 502

7-{2-butyl-4-[4-(2,4-dichloro- phenoxy)-phenyl]-imidazol-1-yl}- 1,2,3,4-tetrahydro-isoquinoline 503

7-(2-butyl-4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-isobutyl-imidazol- 1-yl)-1,2,3,4-tetrahydro-isoquinoline 504

7-[4-(4-benzyloxy-phenyl)-2-butyl- imidazol-1-yl]-1,2,3,4-tetrahydro- isoquinoline hydrochloride hydrochloride 505

9-(2-{4-[2-butyl-1-(1,2,3,4- tetrahydro-isoquinolin-7-yl)-1H- imidazol-4-yl]-phenoxy}-ethyl-9H- carbazole 506

7-{2-butyl-4-[4-(4-methoxy-phenoxy)- phenyl]-imidazol-1-yl}-1,2,3,4- tetrahydro-isoquinoline 507

7-(2-butyl-4-{4-[2-(4-tert-butyl- phenyl)-ethoxy]-phenyl}-imidazol-1- yl)-1,2,3,4-tetrahydro-isoquinoline hydrochloride 508

7-{2-butyl-4-[4-(naphthalen-2- ylmethoxy)-phenyl]-imidazol-1-yl}- 1,2,3,4-tetrahydro-isoquinoline hydrochloride 509

7-{2-butyl-4-[4-(4-trifluoromethyl- phenoxy)-phenyl]-imidazol-1-yl}- 1,2,3,4-tetrahydro-isoquinoline hydrochloride 510

7-(2-butyl-4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-imidazol-1-yl)-1,2,3,4- tetrahydro-isoquinoline 511

[3-(4-{2-(4-Butyl-cyclohexyl)-1-[4-(4- chloro-phenoxy)-phenyl]-1H- imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 512

2-(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}- phenoxy)-ethylamine 513

[3-(4-{2-(trans-4-tert-Butyl- cyclohexyl)-1-[4-(4-chloro-phenoxy)- phenyl]-1H-imidazol-4-yl}-phenoxy)- propyl]-diethyl-amine 514

[3-(4-{2-(cis-4-tert-Butyl-cyclohexyl)- 1-[4-(4-chloro-phenoxy)-phenyl}-1H- imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 515

[2-(4-{2-Butyl-1-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]- 1H-imidazol-4-yl}-phenoxy)-ethyl]- methyl-pyridin-4-yl-amine 516

[2-(4-{1-[4-(4-Fluoro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}- phenoxy)-ethyl]-methyl-pyridin-4-yl- amine 517

[2-(4-{1-[4-(4-Fluoro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}- phenoxy)-ethyl]-methy-(3-methyl- pyridin-4-yl)-amine 518

[2-(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4- yl}-phenoxy)-ethyl]-ethyl-pyridin- 4-yl-amine 519

[2-(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}- phenoxy)-ethyl]-pyridin-4-yl-amine 520

[2-(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}- phenoxy)-ethyl]-bis-pyridin-2- ylmethyl-amine 521

N-[2-(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}- phenoxy)-ethyl]-guanidine 522

2-(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}- phenoxy)-1-(4-pyridin-4-yl-piperazin- 1-yl)-ethanone 523

5-(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}- phenoxymethyl)-pyrrolidin-3-ol 524

3-(4-{1-[4-(4-Fluoro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}- phenoxy)-pyridin-4-ylamine 525

(4-{1-[4-(4-Chloro-phenoxy)-phenyl]- 2-isobutyl-1H-imidazol-4-yl}-phenyl)- pyridin-4-yl-amine 526

2-(4-{1-[4-(4-Fluoro-phenoxy)-phenyl]- 2-isobutyl-1H-imidazol-4-yl}- phenoxymethyl)-3,5-dimethyl- pyridin-4-ylamine 527

1-[2-(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}- phenoxy)-ethyl]-4-pyridin-4-yl- piperazine 528

4-(4-{2-Butyl-4-[4-(3-diethylamino- propoxy)-phenyl]-imidazol-1-yl}- phenoxy)-phenylamine 529

{3-[4-(2-Butyl-4-dibenzofuran-2-yl- imidazol-1-yl)-phenoxy]-propyl}- diethyl-amine 530

N-[4-(4-{2-Butyl-4-[4-(3- diethylamino-propoxy)-phenyl]- imidazol-1-yl}-phenoxy)-phenyl]- benzamide 531

N-[4-(4-{2-Butyl-4-[4-(3- diethylamino-propoxy)-phenyl]- imidazol-1-yl}-phenoxy)-phenyl]- isonicotinamide 532

[2-(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}- phenoxy)-ethyl]-methyl-pyridin-4-yl- amine 533

N-(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-4-yl}- phenyl)-2-dimethylamino-acetamide 534

{3-[4-(4-{4-[3,3-Bis-(4-chloro- phenyl)-allyloxy]-phenyl}-2-isobutyl- imidazol-1-yl)-phenoxy]-propyl}- diethyl-amine 535

{3-[4-(4-{4-[3,3-Bis-(4-fluoro- phenyl)-propoxy]-phenyl}-2-isobutyl- imidazol-1-yl)-phenoxy]-propyl}- diethyl-amine 536

[2-(4-{4-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-imidazol-1-yl}- phenoxy)-ethyl]-methyl-pyridin-4-yl- amine 537

[3-(4-{4-{4-[2-(4-Chloro-phenyl)- ethoxy]-phenyl}-2-[2-(1-methyl- pyridin-3-yl)-ethyl]-imidazol-1-yl} phenoxy)-propyl]-diethylmethyl ammonium iodide 538

[3-(4-{2-(N-BOC-piperidine-4- ylmethyl)-1-[4-(4-chloro-phenoxy)- phenyl]-1H-imidazol-4-yl}-phenoxy)- propyl]-diethyl-amine 539

[3-(4-{2-(Piperidine-4-ylmethyl)-1-[4- (4-chloro-phenoxy)-phenyl]-1H-imidazol- 4-yl}-phenoxy)-propyl]-diethyl-amine 540

[3-(4-{2-(N-ethyl-piperidine-4- ylmethyl)-1-[4-(4-chloro-phenoxy)- phenyl]-1H-imidazol-4-yl}-phenoxy)- propyl}-diethyl-amine 541

[3-(4-{2-(piperidine-4-ylmethyl)-4-[4- (4-chloro-phenoxy)-phenyl]- imidazol-1-yl}-phenoxy)-propyl]- diethyl-amine 542

[3-(4-{2-(N-ethylpiperidine-4- ylmethyl)-4-[4-(4-chloro-phenoxy)- phenyl]-imidazol-1-yl}-phenoxy)- propyl]-diethyl-amine 543

[3-(4-{2-(N-acetylpiperidine-4-yl)-4- [4-(4-chloro-phenoxy)-phenyl]- imidazol-1-yl}-phenoxy)-propyl]- diethyl-amine 544

[3-(4-{2-(piperidine-4-yl)-4-[4-(4- chloro-phenoxy)-phenyl]-imidazol-1- yl}-phenoxy)-propyl]-diethyl-amine 545

[3-(4-{2-(N-Benzylpiperidine-4-yl)-4- [4-(4-chloro-phenoxy)-phenyl]- imidazol-1-yl}-phenoxy)-propyl]- diethyl-amine 546

[3-(4-{2-(N-(2-Pyridylmethyl)- piperidine-4-yl)-4-[4-(4-chloro- phenoxy)-phenyl]-imidazol-1-yl}- phenoxy)-propyl]-diethyl-amine 547

[3-(4-{2-(N-(2-Imidazolylmethyl)- piperidine-4-yl)-4-[4-(4-chloro- phenoxy)-phenyl]-imidazol-1-yl}- phenoxy)-propyl]-diethyl-amine 548

[3-(4-{2-(N-(4- biphenyl)methylpiperidine-4-yl)-4-[4- (4-chloro-phenoxy)-phenyl]-imidazol- 1-yl}-phenoxy)-propyl]-diethyl-amine 549

[3-(4-{2-(N-Cyclohexylpiperidine-4- yl)-4-[4-(4-chloro-phenoxy)-phenyl]- imidazol-1-yl}-phenoxy)-propyl]- diethyl-amine 550

[3-(4-{2-(N-(4-Cyanobenzyl) piperidine-4-yl)-4-[4-(4-chloro- phenoxy)-phenyl]-imidazol-1-yl}- phenoxy)-propyl]-diethyl-amine 551

[3-(4-{2-(N-Ethylpiperidine-4-yl)-4- [4-(4-chloro-phenoxy)-phenyl]- imidazol-1-yl}-phenoxy)-propyl]- diethyl-amine

DEFINITIONS OF TERMS

As used herein, the term “lower” refers to a group having between one and six carbons.

As used herein, the term “alkyl” refers to a straight or branched chain hydrocarbon having from one to ten carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such an “alkyl” group may containing one or more O, S, S(O), or S(O)₂ atoms. Examples of “alkyl” as used herein include, but are not limited to, methyl, n-butyl, t-butyl, n-pentyl, isobutyl, and isopropyl, and the like.

As used herein, the term “alkylene” refers to a straight or branched chain divalent hydrocarbon radical having from one to ten carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such an “alkylene” group may containing one or more O, S, S(O), or S(O)₂ atoms. Examples of “alkylene” as used herein include, but are not limited to, methylene, ethylene, and the like.

As used herein, the term “alkyline” refers to a straight or branched chain trivalent hydrocarbon radical having from one to ten carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of “alkyline” as used herein include, but are not limited to, methine, 1,1,2-ethyline, and the like.

As used herein, the term “alkenyl” refers to a hydrocarbon radical having from two to ten carbons and at least one carbon-carbon double bond, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such an “alkenyl” group may containing one or more O, S, S(O), or S(O)₂ atoms.

As used herein, the term “alkenylene” refers to a straight or branched chain divalent hydrocarbon radical having from two to ten carbon atoms and one or more carbon-carbon double bonds, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such an “alkenylene” group may containing one or more O, S, S(O), or S(O)₂ atoms. Examples of “alkenylene” as used herein include, but are not limited to, ethene-1,2-diyl, propene-1,3-diyl, methylene-1,1-diyl, and the like.

As used herein, the term “alkynyl” refers to a hydrocarbon radical having from two to ten carbons and at least one carbon-carbon triple bond, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such an “alkynyl” group may containing one or more O, S, S(O), or S(O)₂ atoms.

As used herein, the term “alkynylene” refers to a straight or branched chain divalent hydrocarbon radical having from two to ten carbon atoms and one or more carbon-carbon triple bonds, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such an “alkynylene” group may containing one or more O, S, S(O), or S(O)₂ atoms. Examples of “alkynylene” as used herein include, but are not limited to, ethyne-1,2-diyl, propyne-1,3-diyl, and the like.

As used herein, “cycloalkyl” refers to an alicyclic hydrocarbon group optionally possessing one or more degrees of unsaturation, having from three to twelve carbon atoms, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. “Cycloalkyl” includes by way of example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and the like.

As used herein, the term “cycloalkylene” refers to an non-aromatic alicyclic divalent hydrocarbon radical having from three to twelve carbon atoms and optionally possessing one or more degrees of unsaturation, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of “cycloalkylene” as used herein include, but are not limited to, cyclopropyl-1,1-diyl, cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl, cyclohexyl-1,4-diyl, cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, and the like.

As used herein, the term “heterocyclic” or the term “heterocyclyl” refers to a three to twelve-membered heterocyclic ring optionally possessing one or more degrees of unsaturation, containing one or more heteroatomic substitutions selected from S, SO, SO₂, O, or N, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such a ring may be optionally fused to one or more of another “heterocyclic” ring(s) or cycloalkyl ring(s). Examples of “heterocyclic” include, but are not limited to, tetrahydrofuran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine, piperazine, and the like.

As used herein, the term “heterocyclyl containing at least one basic nitrogen atom” refers to a “heterocyclic” “heterocyclyl” group as defined above, wherein said heterocyclyl group contains at least one nitrogen atom flanked by hydrogen, alkyl, alkylene, or alkylyne groups, wherein said alkyl and/or alkylene groups are not substituted by oxo. Examples of “heterocyclyl containing at least one basic nitrogen atom” include, but are not limited to, piperazine-2-yl, pyrrolidine-2-yl, azepine-4-yl,

and the like.

As used herein, the term “heterocyclylene” refers to a three to twelve-membered heterocyclic ring diradical optionally having one or more degrees of unsaturation containing one or more heteroatoms selected from S, SO, SO₂, O, or N, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Such a ring may be optionally fused to one or more benzene rings or to one or more of another “heterocyclic” rings or cycloalkyl rings. Examples of “heterocyclylene” include, but are not limited to, tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl, pyran-2,4-diyl, 1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl, piperidine-2,4-diyl, piperidine-1,4-diyl, pyrrolidine-1,3-diyl, morpholine-2,4-diyl, piperazine-1,4-diyl, and the like.

As used herein, the term “aryl” refers to a benzene ring or to an optionally substituted benzene ring system fused to one or more optionally substituted benzene rings, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy optionally substituted by acyl, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of aryl include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, 1-anthracenyl, and the like.

As used herein, the term “arylene” refers to a benzene ring diradical or to a benzene ring system diradical fused to one or more optionally substituted benzene rings, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of “arylene” include, but are not limited to, benzene-1,4-diyl, naphthalene-1,8-diyl, and the like.

As used herein, the term “heteroaryl” refers to a five-to seven-membered aromatic ring, or to a polycyclic heterocyclic aromatic ring, containing one or more nitrogen, oxygen, or sulfur heteroatoms, where N-oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. For polycyclic aromatic ring systems, one or more of the rings may contain one or more heteroatoms. Examples of “heteroaryl” used herein are furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, quinazoline, benzofuran, benzothiophene, indole, and indazole, and the like.

As used herein, the term “heteroarylene” refers to a five-to seven-membered aromatic ring diradical, or to a polycyclic heterocyclic aromatic ring diradical, containing one or more nitrogen, oxygen, or sulfur heteroatoms, where N-oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions, optionally substituted with substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of substitution being allowed. For polycyclic aromatic ring system diradicals, one or more of the rings may contain one or more heteroatoms. Examples of “heteroarylene” used herein are furan-2,5-diyl, thiophene-2,4-diyl, 1,3,4-oxadiazole-2,5-diyl, 1,3,4-thiadiazole-2,5-diyl, 1,3-thiazole-2,4-diyl, 1,3-thiazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl, pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl, and the like.

As used herein, the term “fused cycloalkylaryl” refers to one or more cycloalkyl groups fused to an aryl group, the aryl and cycloalkyl groups having two atoms in common, and wherein the aryl group is the point of substitution. Examples of “fused cycloalkylaryl” used herein include 5-indanyl, 5,6,7,8-tetrahydro-2-naphthyl,

and the like.

As used herein, the term “fused cycloalkylarylene” refers to a fused cycloalkylaryl, wherein the aryl group is divalent. Examples include

and the like.

As used herein, the term “fused arylcycloalkyl” refers to one or more aryl groups fused to a cycloalkyl group, the cycloalkyl and aryl groups having two atoms in common, and wherein the cycloalkyl group is the point of substitution. Examples of “fused arylcycloalkyl” used herein include 1-indanyl, 2-indanyl, 9-fluorenyl, 1-(1,2,3,4-tetrahydronaphthyl),

and the like.

As used herein, the term “fused arylcycloalkylene” refers to a fused arylcycloalkyl, wherein the cycloalkyl group is divalent. Examples include 9,1-fluorenylene,

and the like.

As used herein, the term “fused heterocyclylaryl” refers to one or more heterocyclyl groups fused to an aryl group, the aryl and heterocyclyl groups having two atoms in common, and wherein the aryl group is the point of substitution. Examples of “fused heterocyclylaryl” used herein include 3,4-methylenedioxy-1-phenyl,

and the like

As used herein, the term “fused heterocyclylarylene” refers to a fused heterocyclylaryl, wherein the aryl group is divalent. Examples include

and the like.

As used herein, the term “fused arylheterocyclyl” refers to one or more aryl groups fused to a heterocyclyl group, the heterocyclyl and aryl groups having two atoms in common, and wherein the heterocyclyl group is the point of substitution. Examples of “fused arylheterocyclyl” used herein include 2-(1,3-benzodioxolyl),

and the like.

As used herein, the term “fused arylheterocyclyl containing at least one basic nitrogen atom” refers to a “fused arylheterocyclyl” group as defined above, wherein said heterocyclyl group contains at least one nitrogen atom flanked by hydrogen, alkyl, alkylene, or alkylyne groups, wherein said alkyl and/or alkylene groups are not substituted by oxo. Examples of “fused arylheterocyclyl containing at least one basic nitrogen atom” include, but are not limited to,

and the like.

As used herein, the term “fused arylheterocyclylene” refers to a fused arylheterocyclyl, wherein the heterocyclyl group is divalent. Examples include

and the like.

As used herein, the term “fused cycloalkylheteroaryl” refers to one or more cycloalkyl groups fused to a heteroaryl group, the heteroaryl and cycloalkyl groups having two atoms in common, and wherein the heteroaryl group is the point of substitution. Examples of “fused cycloalkylheteroaryl” used herein include 5-aza-6-indanyl,

and the like.

As used herein, the term “fused cycloalkylheteroarylene” refers to a fused cycloalkylheteroaryl, wherein the heteroaryl group is divalent. Examples include

and the like.

As used herein, the term “fused heteroarylcycloalkyl” refers to one or more heteroaryl groups fused to a cycloalkyl group, the cycloalkyl and heteroaryl groups having two atoms in common, and wherein the cycloalkyl group is the point of substitution. Examples of “fused heteroarylcycloalkyl” used herein include 5-aza-1-indanyl,

and the like.

As used herein, the term “fused heteroarylcycloalkylene” refers to a fused heteroarylcycloalkyl, wherein the cycloalkyl group is divalent. Examples include

and the like.

As used herein, the term “fused heterocyclylheteroaryl” refers to one or more heterocyclyl groups fused to a heteroaryl group, the heteroaryl and heterocyclyl groups having two atoms in common, and wherein the heteroaryl group is the point of substitution. Examples of “fused heterocyclylheteroaryl” used herein include 1,2,3,4-tetrahydro-beta-carbolin-8-yl,

and the like.

As used herein, the term “fused heterocyclylheteroarylene” refers to a fused heterocyclylheteroaryl, wherein the heteroaryl group is divalent. Examples include

and the like.

As used herein, the term “fused heteroarylheterocyclyl” refers to one or more heteroaryl groups fused to a heterocyclyl group, the heterocyclyl and heteroaryl groups having two atoms in common, and wherein the heterocyclyl group is the point of substitution. Examples of “fused heteroarylheterocyclyl” used herein include -5-aza-2,3-dihydrobenzofuran-2-yl,

and the like.

As used herein, the term “fused heteroarylheterocyclyl containing at least one basic nitrogen atom” refers to a “fused heteroarylheterocyclyl” group as defined above, wherein said heterocyclyl group contains at least one nitrogen atom flanked by hydrogen, alkyl, alkylene, or alkylyne groups, wherein said alkyl and/or alkylene groups are not substituted by oxo. Examples of “fused heteroarylheterocyclyl containing at least one basic nitrogen atom” include, but are not limited to,

and the like.

As used herein, the term “fused heteroarylheterocyclylene” refers to a fused heteroarylheterocyclyl, wherein the heterocyclyl group is divalent. Examples include

and the like.

As used herein, the term “acid isostere” refers to a substituent group which will ionize at physiological pH to bear a net negative charge. Examples of such “acid isosteres” include but are not limited to heteroaryl groups such as but not limited to 1H-tetrazole-5-yl, or 2H-tetrazole-5-yl. Such acid isosteres include but are not limited to heterocyclyl groups such as but not limited to imidazolidine-2,4-dione-5-yl, imidazolidine-2,4-dione-1-yl, 1,3-thiazolidine-2,4-dione-5-yl, or 5-hydroxy-4H-pyran-4-on-2-yl.

As used herein, the term “direct bond”, where part of a structural variable specification, refers to the direct joining of the substituents flanking (preceding and succeeding) the variable taken as a “direct bond”. Where two or more consecutive variables are specified each as a “direct bond”, those substituents flanking (preceding and succeeding) those two or more consecutive specified “direct bonds” are directly joined.

As used herein, the term “alkoxy” refers to the group R_(a)O—, where R_(a) is alkyl.

As used herein, the term “alkenyloxy” refers to the group R_(a)O—, where R_(a) is alkenyl.

As used herein, the term “alkynyloxy” refers to the group R_(a)O—, where R_(a) is alkynyl.

As used herein, the term “alkylsulfanyl” refers to the group R_(a)S—, where R_(a) is alkyl.

As used herein, the term “alkenylsulfanyl” refers to the group R_(a)S—, where R_(a) is alkenyl.

As used herein, the term “alkynylsulfanyl” refers to the group R_(a)S—, where R_(a) is alkynyl.

As used herein, the term “alkylsulfenyl” refers to the group R_(a)S(O)—, where R_(a) is alkyl.

As used herein, the term “alkenylsulfenyl” refers to the group R_(a)S(O)—, where R_(a) is alkenyl.

As used herein, the term “alkynylsulfenyl” refers to the group R_(a)S(O)—, where R_(a) is alkynyl.

As used herein, the term “alkylsulfonyl” refers to the group R_(a)SO₂—, where R_(a) is alkyl.

As used herein, the term “alkenylsulfonyl” refers to the group R_(a)SO₂—, where R_(a) is alkenyl.

As used herein, the term “alkynylsulfonyl” refers to the group R_(a)SO₂—, where R_(a) is alkynyl.

As used herein, the term “acyl” refers to the group R_(a)C(O)—, where R_(a) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocyclyl.

As used herein, the term “aroyl” refers to the group R_(a)C(O)—, where R_(a) is aryl.

As used herein, the term “heteroaroyl” refers to the group R_(a)C(O)—, where R_(a) is heteroaryl.

As used herein, the term “alkoxycarbonyl” refers to the group R_(a)OC(O)—, where R_(a) is alkyl.

As used herein, the term “acyloxy” refers to the group R_(a)C(O)O—, where R_(a) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocyclyl.

As used herein, the term “alkoxycarbonyl” refers to the group R_(a)OC(O)—, where R_(a) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or heterocyclyl.

As used herein, the term “aryloxycarbonyl” refers to the group R_(a)OC(O)—, where R_(a) is aryl or heteroaryl.

As used herein, the term “aroyloxy” refers to the group R_(a)C(O)O—, where R_(a) is aryl.

As used herein, the term “heteroaroyloxy” refers to the group R_(a)C(O)O—, where R_(a) is heteroaryl.

As used herein, the term “optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) which occur and events that do not occur.

As used herein, the term “substituted” refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.

As used herein, the terms “contain” or “containing” can refer to in-line substitutions at any position along the above defined alkyl, alkenyl, alkynyl or cycloalkyl substituents with one or more of any of O, S, SO, SO₂, N, or N-alkyl, including, for example, —CH₂—O—CH₂—, —CH₂—SO₂—CH₂—, —CH₂—NH—CH₃ and so forth.

Whenever the terms “alkyl” or “aryl” or either of their prefix roots appear in a name of a substituent (e.g. arylalkoxyaryloxy) they shall be interpreted as including those limitations given above for “alkyl” and “aryl”. Alkyl or cycloalkyl substituents shall be recognized as being functionally equivalent to those having one or more degrees of unsaturation. Designated numbers of carbon atoms (e.g. C₁₋₁₀) shall refer independently to the number of carbon atoms in an alkyl, alkenyl or alkynyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which the term “alkyl” appears as its prefix root.

As used herein, the term “oxo” shall refer to the substituent ═O.

As used herein, the term “halogen” or “halo” shall include iodine, bromine, chlorine and fluorine.

As used herein, the term “mercapto” shall refer to the substituent —SH.

As used herein, the term “carboxy” shall refer to the substituent —COOH.

As used herein, the term “cyano” shall refer to the substituent —CN.

As used herein, the term “aminosulfonyl” shall refer to the substituent —SO₂NH₂.

As used herein, the term “carbamoyl” shall refer to the substituent —C(O)NH₂.

As used herein, the term “sulfanyl” shall refer to the substituent —S—.

As used herein, the term “sulfenyl” shall refer to the substituent —S(O)—.

As used herein, the term “sulfonyl” shall refer to the substituent —S(O)₂—.

As used herein, the term “solvate” is a complex of variable stoichiometry formed by a solute (in this invention, a compound of Formula (I)) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Solvents may be, by way of example, water, ethanol, or acetic acid.

As used herein, the term “biohydrolyzable ester” is an ester of a drug substance (in this invention, a compound of Formula (I)) which either a) does not interfere with the biological activity of the parent substance but confers on that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principle. The advantage is that, for example, the biohydrolyzable ester is orally absorbed from the gut and is transformed to (I) in plasma. Many examples of such are known in the art and include by way of example lower alkyl esters (e.g., C₁-C₄), lower acyloxyalkyl esters, lower alkoxyacyloxyalkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters.

As used herein, the term “biohydrolyzable amide” is an amide of a drug substance (in this invention, a compound of general Formula (I)) which either a) does not interfere with the biological activity of the parent substance but confers on that substance advantageous properties in vivo such as duration of action, onset of action, and the like, or b) is biologically inactive but is readily converted in vivo by the subject to the biologically active principle. The advantage is that, for example, the biohydrolyzable amide is orally absorbed from the gut and is transformed to (I) in plasma. Many examples of such are known in the art and include by way of example lower alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.

As used herein, the term “prodrug” includes biohydrolyzable amides and biohydrolyzable esters and also encompasses a) compounds in which the biohydrolyzable functionality in such a prodrug is encompassed in the compound of Formula (I): for example, the lactam formed by a carboxylic group in R₂ and an amine in R₄, and b) compounds which may be oxidized or reduced biologically at a given functional group to yield drug substances of Formula (I). Examples of these functional groups include, but are not limited to, 1,4-dihydropyridine, N-alkylcarbonyl-1,4-dihydropyridine, 1,4-cyclohexadiene, tert-butyl, and the like.

The term “pharmacologically effective amount” or shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, animal or human that is being sought by a researcher or clinician. This amount can be a therapeutically effective amount. The term “therapeutically effective amount” shall mean that amount of a drug or pharmaceutical agent that will elicit the therapeutic response of an animal or human that is being sought.

The term “treatment” or “treating” as used herein, refers to the full spectrum of treatments for a given disorder from which the patient is suffering, including alleviation of one, most of all symptoms resulting from that disorder, to an outright cure for the particular disorder or prevention of the onset of the disorder.

The present invention also provides a method for the synthesis of compounds useful as intermediates in the preparation of compounds of Formula (I) along with methods for the preparation of compounds of Formula (I). Unless otherwise indicated, variables refer to those for Formula (I).

An aldehyde (1) (Scheme 1) may be condensed with a diamine compound (2) in a solvent such as ethanol at a temperature of from 25 to 100 degrees Celsuis, to obtain the product benzimidazole (3), where the intermediate adduct undergoes spontaneous oxidation. Alternately, the acid (1a) may be coupled with the diamine compound (2) employing a reagent such as HBTU to afford (2a). The reaction may also afford some of the compound where the carboxylic acid has coupled to the secondary aniline nitrogen. Either product (2a) may be cyclized to (3). One nonlimiting method is to heat (2a) in a solvent such as acetic acid at a temperature of from 25 to 100 degrees Celsuis, to obtain the cyclized product (3). Ar₁ is a group such as but not limited to an optionally substituted aryl or heteroaryl ring system.

Where R₅₂ is aryl, heteroaryl, or contains an aryl or heteroaryl group possessing a phenolic substituent, or where R₅₂ possesses a free hydroxyl group, an aldehyde of formula (4) (Scheme 2) may be treated with an optionally substituted alkyl halide R₅₁-LG₁ and a base such as potassium carbonate, in a solvent such as DMF, at a temperature of from 0 to 120° C., to afford (5). LG₁ represents a nucleofugal group such as iodide, bromide, methanesulfonate, or toluenesulfonate (Scheme 2). Where R₅₃ in (6) represents an aryl or heteroaryl ring system, direct treatment of (6) in the presence of a base such as DIEA or TEA with an aryl or heteroaryl phenol Ar₂—OH provides (7), where the Ar₂—O— substituent is bonded to the same atom as the F in (6).

In Scheme 3, an aldehyde (8) posessing two free hydroxyl groups, two free phenolic groups, of a combination of phenolic and hydroxyl groups may be treated with two equivalents of an alkylating agent R₅₁-LG₁, in the presence of a suitable base such as potassium carbonate or DIEA, in a solvent such as DMF, to afford (9). Alternately, where R₅₃ is an aryl ring posessing ortho and para hydroxyl groups relative to the aldehyde group, treatment of (8) with one equivalent of base and an alkylating agent R₅₁-LG₁ in the presence of a suitable base such as DIEA of potassium carbonate, followed by treatment with a second alkylating agent R₅₄-LG₂ in the presence of base, affords (10). The ortho, para difluoro aldehyde (11), where R₅₃ is a heteroaryl or aryl ring, may be treated with an alcohol R₅₅—OH in the presence of base such as DIEA, followed by treatment with a phenol Ar₃—OH in the presence of a base such as DIEA or potassium carbonate, to afford (12).

Scheme 4 describes the synthesis of substituted arylenediamines.

In Scheme 4, an ortho-fluoro nitrophenol such as (13) may be alkylated with an alkyl halide or other alkylating agent R₅₆-LG₁, in the presence of an alkali metal carbonate as base in a solvent such as DMF or acetonitrile. LG₁ may represent a nucleofugal group such as iodide, bromide, methanesulfonate, and the like. In this transformation, R₅₆ is a group such as but not limited to alkyl. The intermediate may be treated with an amine R₂—NH₂ in the presence or absence of a tertiary amine base, in a solvent such as THF, at a temperature of from 0° C. to 100° C., to afford (14). Reduction of the nitro group in (14) may be accomplished by treatment of (14) in acidic or neutral ethanol with stannous chloride at a temperature of from 25° C. to 100° C. to afford the aniline (15). Alternately, (14) may be reduced by treatment of (14) with a noble metal catalyst such as palladium on charcoal and a hydrogen source such as gaseous hydrogen or ammonium formate, in a solvent such as ethanol, at a temperature of from 25° C. to 80° C., to afford (15).

The difluoronitroaromatic compound (16) may be employed in similar manner, where in (16), one fluoro is ortho to the nitro group. Treatment of (16) with the one equivalent of amine R₂—NH₂ gives preferential substitution of the ortho fluorine. The second fluorine in the intermediate may be substituted by an alcohol R₅₇—OH to afford (17). In this instance, R₅₇ may also be aryl. Reduction of the nitro group in (17) as before with stannous chloride provides (18). Ar₄ represents a group such as but not limited to aryl or heteroaryl.

Scheme 5 describes synthesis of aryl diamines. The 2,4,6-trifluoronitroaromatic compound (19) may be treated with one equivalent of an amine R₂—NH2 to afford the product of substitution at one ortho fluoro; excess R₅₈—OH may then be employed in the presence of a base such as potassium tert-butoxide or sodium hydride to afford (20). Reduction of the nitro group as for Scheme 4 affords the aniline (21). Similarly, a 3,5-difluorophenolic aromatic compound (22) may be nitrated under strong nitrating conditions, e.g. fuming nitric acid, to afford the ortho nitro phenol (23) along with the para nitrophenol (24). Each individually may be processed by sequential phenol alkylation, ortho fluoro displacement by R₂—NH₂, and para or ortho fluorodisplacement by R₅₈—OH, to afford (25) and (26) after reduction, following chemistries in the preceding general procedures. Ar₅ represents a group such as but not limited to aryl or heteroaryl.

Scheme 6 describes the synthesis of mono and di alkoxy-substituted aminoaryl and aminoheteroaryl compounds. A fluoronitroaromatic (27), where F is preferably ortho or para to the nitro, may be treated with an alcohol or phenol R₆₀—OH and a base such as potassium tert-butoxide or sodium hydride, to afford the ipso adduct. Reduction of the nitro group to amino following preceding methods affords (28). Similarly, displacement of the fluoro groups in (29) with R₆₀—OH followed by reduction as before give (30). The nitro compound (31) may be treated with a base and R₆₁-LG₁ to afford the alkylation product, then treated with R₆₀—OH and a base, then reduced as above to give (32). Alternately, (33) may be processed similarly to give (32). Ar₆ represents a group such as but not limited to aryl or heteroaryl.

Scheme 7 describes a general synthesis of imidazoles. An aniline containing a basic side chain (—O—R₆₂) (40) may be coupled with a bromoketone containing a non-basic side chain (—O—R₆₃) (41) to give the aminoketone (42), which may then be treated with acetic acid, heat, an aldehyde R₁—CHO, and ammonium acetate to afford (43). Alternately, (42) may be treated with an acid chloride R₁—COCl to afford (44), which may subsequently be treated with ammonium acetate, acetic acid and heat to afford (43). Ar₇ and Ar₈ represent groups such as but not limited to aryl or heteroaryl.

Scheme 8 describes another general synthesis of imidazoles. An aniline containing a non-basic side chain (45) may be coupled with a bromoketone containing a basic side chain (46) to give the aminoketone (47), which may then be treated with acetic acid, heat, an aldehyde R₁—CHO, and ammonium acetate to afford (48). Alternately, (42) may be treated with an acid chloride R₁—COCl to afford (49), which may subsequently be treated with ammonium acetate, acetic acid and heat to afford (43). Ar₇ and Ar₈ represent groups such as but not limited to aryl or heteroaryl.

Scheme 9 describes another general synthesis of imidazoles. An aniline containing a basic side chain (40) may be coupled with a bromoketone (50) to give the aminoketone (51), which may then be treated with an acid chloride R₁—COCl to afford (52), which may subsequently be treated with ammonium acetate, acetic acid and heat to afford (53). The phenol is then alkylated with a alkylating agent R₆₃-LG₅ to generate the desired imidazole (54). R₆₃ is a group such as but not limited to substituted alkyl, and LG₅ is a leaving group such as iodide or methanesulfonate. Ar₇ and Ar₈ represent groups such as but not limited to aryl or heteroaryl.

Scheme 10 describes another general synthesis of imidazoles. An aniline containing a hydrophobic side chain (40) may be coupled with a bromoketone (55) to give the aminoketone (56), which may then be treated with an acid chloride R₁—COCl to afford (57), which may subsequently be treated with ammonium acetate, acetic acid and heat to afford (58). The phenol is then deprotected; PG, may be a group sych as but not limited to benzyl, which may be removed with treatment with hydrogen over palladium on carbon. The free phenolic group is subsequently alkylated with an alkylating agent R₆₃-LG₅ to generate the desired imidazole (59). R₆₃ is a group such as but not limited to substituted alkyl, and LG₅ is a leaving group such as iodide or methanesulfonate.

Scheme 11 describes the symnthesis of diones or bromoketones. A aryl ketone (60) may be treated with base and an alkylating agent R₆₄-LG₆ to generate the phenyl ether. R₆₄ is a group such as but not limited to substituted alkyl, and LG₆ is a leaving group such as iodide or methanesulfonate. The product may be brominated with a reagent such as but not limited to pyrrolidinium hydrotribromide, to (61) and the bromide may be oxidized by treatment with DMSO to afford (62). (63) may be treated with Ar₁₀—OH and base, followed by bromination, to afford (64). Oxidation as before gives the dione (65). Ar₉ is a group such as but not limited to aryl or heteroaryl.

Scheme 12 describes the synthesis of imidazoles. (66) may be treated with (67) and an aldehyde R₁—CHO to afford (68). Alternately, (66) may be coupled with the bromoketone (70) to give the aminoketome (71), which may be treated with acetic acid, heat, an aldehyde R₁—CHO, and ammonium acetate to afford (68). Ar₁₁ and Ar₁₂ are groups such as but not limited to aryl or heteroaryl.

Scheme 13 describes the synthesis of imidazoles. A dione (72) may be treated with R₁—CHO and ammonium acetate-acetic acid to afford (74). Alternately, an amine R₂—NH₂ may be used in place of ammonium acetate to give (75).

Scheme 14 describes another synthesis of imidazoles. (76) may be coupled with the bromoketone (77) to give the aminoketone (78), which may be treated with acetic acid, heat, an aldehyde R₁—CHO, and ammonium acetate to afford (80). Alternately, (78) may be treated with an acid chloride R₁—COCl to afford (79), which may subsequently be treated with ammonium acetate, acetic acid and heat to afford (80). The group R₆₈ may be an amino protecting group, such as BOC, which may be removed by treatment of (80) with TFA. The amine may be directly alkylated or reductively alkylated by methods known in the art. For example, treatment of the NH compound with acetaldehyde and sodium cyanoborohydride in a solvent such as acetic acid affords (80) where R₆₈ is ethyl. Ar₁₂ is a group such as but not limited to aryl or heteroaryl.

Scheme 15 describes the synthesis of imidazoles. A dione (81) may be treated with R₁—CHO and an amine (76) in acetic acid, in the presence of ammonium acetate, at a temperature of from 50 to 140° C., to afford (83). If the group R₆₈ is an amine protecting group, then said protecting group may be removed and the nitrogen alkylated as described in Scheme 14.

The term “amino protecting group” as used herein refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups on the compound. Examples of such amino-protecting groups include the formyl group, the trityl group, the phthalimido group, the trichloroacetyl group, the chloroacetyl, bromoacetyl and iodoacetyl groups, urethane-type blocking groups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxy-carbonyl, 2-(4-xenyl)iso-propoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluoyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl, 2(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, 9-fluorenylmethoxycarbonyl (“FMOC”), t-butoxycarbonyl (“BOC”), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl, isobornyloxycarbonyl, 1-piperidyloxycarbonyl and the like; the benzoylmethylsulfonyl group, the 2-(nitro)phenylsulfenyl group, the diphenylphosphine oxide group and like amino-protecting groups. The species of amino-protecting group employed is not critical so long as the derivatized amino group is stable to the condition of subsequent reaction(s) on other positions of the compound of Formula (I) and can be removed at the desired point without disrupting the remainder of the molecule. Preferred amino-protecting groups are the allyloxycarbonyl, the t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, and the trityl groups. Similar amino-protecting groups used in the cephalosporin, penicillin and peptide art are also embraced by the above terms. Further examples of groups referred to by the above terms are described by J. W. Barton, “Protective Groups In Organic Chemistry”, J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, and T. W. Greene, “Protective Groups in Organic Synthesis”, John Wiley and Sons, New York, N.Y., 1981. The related term “protected amino” or “protected amino group” defines an amino group substituted with an amino-protecting group discussed above.

The term “hydroxyl protecting group” as used herein refers to substituents of the alcohol group commonly employed to block or protect the alcohol functionality while reacting other functional groups on the compound. Examples of such alcohol -protecting groups include the 2-tetrahydropyranyl group, 2-ethoxyethyl group, the trityl group, the trichloroacetyl group, urethane-type blocking groups such as benzyloxycarbonyl, and the trialkylsilyl group, examples of such being trimethylsilyl, tert-butyldimethylsilyl, phenyldimethylsilyl, triiospropylsilyl and thexyldimethylsilyl. The choice of alcohol-protecting group employed is not critical so long as the derivatized alcohol group is stable to the condition of subsequent reaction(s) on other positions of the compound of the formulae and can be removed at the desired point without disrupting the remainder of the molecule. Further examples of groups referred to by the above terms are described by J. W. Barton, “Protective Groups In Organic Chemistry”, J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, and T. W. Greene, “Protective Groups in Organic Synthesis”, John Wiley and Sons, New York, N.Y., 1981. The related term “protected hydroxyl” or “protected alcohol” defines a hydroxyl group substituted with a hydroxyl-protecting group as discussed above.

The term “carboxyl protecting group” as used herein refers to substituents of the carboxyl group commonly employed to block or protect the —OH functionality while reacting other functional groups on the compound. Examples of such alcohol -protecting groups include the 2-tetrahydropyranyl group, 2-ethoxyethyl group, the trityl group, the allyl group, the trimethylsilylethoxymethyl group, the 2,2,2-trichloroethyl group, the benzyl group, and the trialkylsilyl group, examples of such being trimethylsilyl, tert-butyldimethylsilyl, phenyldimethylsilyl, triiospropylsilyl and thexyldimethylsilyl. The choice of carboxyl protecting group employed is not critical so long as the derivatized alcohol group is stable to the condition of subsequent reaction(s) on other positions of the compound of the formulae and can be removed at the desired point without disrupting the remainder of the molecule. Further examples of groups referred to by the above terms are described by J. W. Barton, “Protective Groups In Organic Chemistry”, J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, and T. W. Greene, “Protective Groups in Organic Synthesis”, John Wiley and Sons, New York, N.Y., 1981. The related term “protected carboxyl” defines a carboxyl group substituted with a carboxyl-protecting group as discussed above.

The general procedures used in the methods of the present invention are described below.

Methods

LC-MS data is obtained using gradient elution on a Waters 600 controller equipped with a 2487 dual wavelength detector and a Leap Technologies HTS PAL Autosampler using an YMC Combiscreen ODS-A 50×4.6 mm column. A three minute gradient is run from 25% B (97.5% acetonitrile, 2.5% water, 0.05% TFA) and 75% A (97.5% water, 2.5% acetonitrile, 0.05% TFA) to 100% B. The mass spectrometer used is a Micromass ZMD instrument. All data is obtained in the positive mode unless otherwise noted. ¹H NMR and ¹³C NMR data is obtained on a Varian 400 MHz spectrometer.

Abbreviations used in the Examples are as follows: APCl=atmospheric pressure chemical ionization BOC=tert-butoxycarbonyl BOP=(1-benzotriazolyloxy)tris(dimethylamino)phosphonium hexafluorophosphate d=day DIAD=diisopropyl azodicarboxylate DCC=dicyclohexylcarbodiimide DCM=dichloromethane DIC=diisopropylcarbodiimide DIEA=diisopropylethylamine

DMA=N,N-dimethylacetamide

DMAP=dimethylaminopyridine DME=1,2 dimethoxyethane

DMF=N,N-dimethylformamide

DMPU=1,3-dimethypropylene urea DMSO=dimethylsulfoxide Et=ethyl iPr=isopropyl Bn=benzyl Me=methyl tBu=tert-butyl Pr=propyl Bu=butyl iBu=isobutyl EDC=1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride EDTA=ethylenediamine tetraacetic acid ELISA=enzyme-linked immunosorbent assay ESI=electrospray ionization ether=diethyl ether EtOAc=ethyl acetate FBS=fetal bovine serum g=gram h=hour HBTU=O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate HMPA=hexamethylphosphoric triamide HOBt=1-hydroxybenzotriazole Hz=hertz i.v.=intravenous kD=kiloDalton L=liter LAH=lithium aluminum hydride LDA=lithium diisopropylamide LPS=lipopolysaccharide M=molar m/z=mass to charge ratio mbar=millibar MeOH=methanol mg=milligram min=minute mL=milliliter mM=millimolar mmol=millimole mol=mole mp=melting point MS=mass spectrometry N=normal NMM=N-methylmorpholine, 4-methylmorpholine NMR=nuclear magnetic resonance spectroscopy p.o.=per oral PS-carbodiimide=N-cyclohexylcarbodiimide-N′-propyloxymethyl polystyrene PBS=phosphate buffered saline solution PMA=phorbol myristate acetate ppm=parts per million psi=pounds per square inch R_(f)=relative TLC mobility rt=room temperature s.c.=subcutaneous SPA=scintillation proximity assay TEA=triethylamine TFA=trifluoroacetic acid THF=tetrahydrofuran THP=tetrahydropyranyl TLC=thin layer chromatography TMSBr=bromotrimethylsilane, trimethylsilylbromide T_(r)=retention time

General Synthesis of Monoalkoxybenzaldehydes: General Procedure A

To a stirred solution of a 2-, 3-, or 4-hydroxybenzaldehyde (2 mmol) in DMF (6 mL) at rt solid K₂CO₃ (4 mmol) is added. An alkyl halide or mesylate (prepared from the corresponding alcohol and methanesulfonyl chloride) (2.2 mmol) is added to the reaction mixture and heated to 80° C. until the reaction is complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture is poured into EtOAc (20 ml) and washed with water (2×10 ml) and brine (15 ml). The organic layer is dried over magnesium sulfate and after removal of the drying agent, the solvent is removed under high vacuum to afford the desired product. The crude product may be used for further transformation without any purification or after purifying using silica gel column chromatography.

General Synthesis of Monoaryloxybenzaldehydes: General Procedure B

To a stirred solution of a 2-, 3-, or 4-fluorobenzaldehyde (2 mmol) in DMF (6 mL) at rt requisite phenol (2.2) is added followed by solid K₂CO₃ (3 mmol). The reaction mixture is heated to 100° C. until the reaction is complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture is poured into EtOAc (20 ml) and washed with water (2×10 ml) and brine (15 ml). The organic layer is dried over magnesium sulfate and after removal of the drying agent, the solvent is removed under high vacuum to afford the desired product. The crude product may be used for further transformation without any purification or after purifying using silica gel column chromatography.

General Synthesis of Homosubstituted 2,4-Dialkoxybenzaldehydes: General Procedure C

To a stirred solution of 2,4-dihydroxybenzaldehyde (2 mmol) in DMF (8 mL) at rt solid Cs₂CO₃ (6 mmol) is added. An alkyl halide or mesylate (prepared from the corresponding alcohol and methanesulfonyl chloride, see General Procedure P2) (4.4 mmol) is added to the reaction mixture and heated to 80° C. until the reaction is complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture is poured into EtOAc (20 ml) and washed with water (2×10 ml) and brine (15 ml). The organic layer is dried over magnesium sulfate and after removal of the drying agent, the solvent is removed under high vacuum to afford the desired product. The crude product may be used for further transformation without any purification or after purifying using silica gel column chromatography.

General Synthesis of Heterosubstituted 2,4-Dialkoxybenzaldehydes: General Procedure D1

To a stirred solution of 2,4-dihydroxybenzaldehyde (2.2 mmol) in DMF (5 mL) at rt solid KHCO₃ (2.2 mmol) is added. An alkyl halide or mesylate (prepared from the corresponding alcohol and methanesulfonyl chloride, see General Procedure P2) (2.0 mmol) is added to the reaction mixture and heated at 130° C. for 4 h. After cooling to rt, the reaction mixture is treated with cold H₂O (15 mL), and extracted with EtOAc (2×10 mL). The combined organic layers is washed with brine, and dried over sodium sulfate. The crude product is purified by flash chromatography to provide the 2-hydroxy-4-alkoxybenzaldehyde intermediate.

General Procedure D2

To a stirred solution of aforementioned 2-hydroxy-4-alkoxybenzaldehyde intermediate (2 mmol) in DMSO (5 mL) at rt solid Cs₂CO₃ (3 mmol) is added. An alkyl halide or mesylate (prepared from the corresponding alcohol and methanesulfonyl chloride, see General Procedure P2) (3 mmol) is added to the reaction mixture and heated to 90° C. until the reaction is complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture is treated with cold H₂O (15 mL), and extracted with EtOAc (2×10 mL). The combined organic layers is washed with H₂O (10 mL) and brine (10 mL) and dried over sodium sulfate. After removal of the drying agent, the solvent is removed under high vacuum to afford the desired product. The crude product may be used for further transformation without any purification or after purifying using silica gel column chromatography.

General Synthesis of 2-Alkoxy-4-Aryloxybenzaldehydes: General Procedure E

A solution of 2,4-difluorobenzaldehyde (2 mmol) in DMF (2 mL) is added dropwise to a precooled (0° C.) solution of sodium alkoxide (2 mmol) in DMF (6 ml) [prepared by stirring a mixture of sodium hydride (2 mmol), and the corresponding alcohol (2 mmol) in DMF]. The resulting reaction mixture is warmed to rt and stirred for an additional 3 h. To the same reaction vessel, solid potassium carbonate (2 mmol) and requisite phenol (2 mmol)) is introduced and the reaction mixture is heated at 90° C. in an oil bath for 24. After cooling to rt, the reaction mixture is poured into EtOAc (20 ml) and washed with water (2×10 ml) and brine (15 ml). The organic layer is dried over magnesium sulfate and after removal of the drying agent, the solvent is removed under high vacuum to afford the desired product. The crude product may be used for further transformation without any purification or after purifying using silica gel column chromatography.

General Synthesis of Monoalkoxy Ortho-Phenylenediamines: Method A: General Procedure F1

To a stirred solution of 3-fluoro-4-nitrophenol (4 mmol) in DMF (6 mL) at rt solid K₂CO₃ (8 mmol) is added. An alkyl halide or mesylate (prepared from the corresponding alcohol and methanesulfonyl chloride, see General Procedure P2) (4.4 mmol) is added to the reaction mixture and heated to 80° C. until the reaction is complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture is poured into EtOAc (40 ml) and washed with water (2×20 ml) and brine (30 ml). The organic layer is dried over magnesium sulfate and after removal of the drying agent, the solvent is removed under vacuum to afford the desired product. The crude product may be used for further transformation without any purification or after purifying using silica gel column chromatography.

General Procedure F2

To a stirred solution of 2-fluoro-4-alkoxynitrobenzene (2 mmol) obtained above, TEA (4 mmol) in DMF (5 mL) is added dropwise a solution of requisite alkylamine (2.2 mmol) in DMF (2 mL) at rt within 15 min, and then stirred at rt for 5 h. The reaction mixture is treated with cold H₂O (10 mL), and extracted with EtOAc (2×15 mL), The combined organic layers is washed with H₂O (10 mL) and brine (10 mL) and dried over sodium sulfate. After removal of the drying agent, the solvent is removed under high vacuum to afford the desired 2-alkylamino-4-alkoxynitrobenzene intermediate. The crude product may be used for further transformation without any purification or after purifying using silica gel column chromatography.

Method B: General Procedure G1

To a stirred solution of 2,4-difluoronitrobenzene (2 mmol), TEA (4 mmol) in DMF (5 mL) is added dropwise a solution of requisite alkylamine (2.2 mmol) in DMF (2 mL) at rt within 15 min, and then stirred at rt for 5 h. The reaction mixture is treated with cold H₂O (10 mL), and extracted with EtOAc (2×15 mL), The combined organic layers is washed with H₂O (10 mL) and brine (10 mL) and dried over sodium sulfate. After removal of the drying agent, the solvent is removed under high vacuum to afford the desired 2-alkylamino-4-fluoronitrobenzene. The crude product may be used for further transformation without any purification or after purifying using silica gel column chromatography.

General Procedure G2

To a stirred solution of 2-alkylamino-4-fluoronitrobenzene as obtained above (2.0 mmol) in anhydrous THF (4 mL), an alcohol (2.4 mmol) is added followed by powdered KOBu^(t) (2.4 mmol) in one portion at rt and under the N₂ stream. The reaction mixture is then refluxed until the reaction is complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture is treated with cold H₂O (15 mL), and extracted with EtOAc (2×10 mL). The combined organic layers is washed with brine, and dried over sodium sulfate. Evaporation of the solvent in vacuo afforded 2-alkylamino-4-alkoxynitrobenzene intermediate. The crude product may be used for further transformation without any purification or after purifying using silica gel column chromatography.

Reduction of Monoalkoxy Nitrobenzenes: General Procedure H

The nitro intermediate (2 mmol) obtained above as in Method A or B is dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until the reaction is complete as indicated by TLC or HPLC. The reaction mixture is then filtered through a celite pad to remove the catalyst. The solvent is removed under high vacuum to afford the desired diamine, which is used directly for further transformation without further purification.

General Procedure I

To a stirred solution of afforded 2-alkylamino-4-alkoxynitrobenzene intermediate [as obtained in (b)](2 mmol) in EtOH (20 mL), SnCl₂.2H₂O (8 mmol) is added and the mixture is refluxed until the reaction is complete as indicated by TLC or HPLC. After completion of the reduction, the solvent is removed in vacuo, and the residue is treated with saturated NaHCO₃ to pH ˜8. The resulting yellow suspension is extracted with DCM (2×20 mL), washed with brine, and dried. The solvent is removed under high vacuum to afford the desired diamine, which is used directly for further transformation without further purification.

General Synthesis of Homo Disubstituted Dialkoxy Ortho-Phenylenediamines: General Procedure J1

To a stirred solution of 2,4,6-trifluoronitrobenzene (3.0 mmol) and triethylamine (6.0 mmol) in DMF (6 mL), a solution of alkyl amine (3.0 mmol) in DMF (2 mL) is added dropwise at rt within 15 min, and then stirred at rt for 5 h. The reaction mixture is treated with cold H₂O (10 mL), and extracted with EtOAc (2×15 mL), The combined organic layers is washed with H2O (10 mL) and brine (10 mL) and dried over sodium sulfate. After removal of the drying agent, the solvent is removed under high vacuum to afford the desired 2-alkylamino-4,6-difluoronitrobenzene. The crude product may be used for further transformation without any purification or after purifying using silica gel column chromatography.

General Procedure J2

To a stirred solution of 2-alkylamino-4,6-difluoronitrobenzene as obtained above (2.0 mmol) in anhydrous THF (4 mL), an alcohol (4.4 mmol) is added followed by powdered KOBu^(t) (4.4 mmol) in one portion at rt and under the N₂ stream. The reaction mixture is then refluxed until the reaction is complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture is treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers is washed with brine, and dried over sodium sulfate. Evaporation of the solvent in vacuo afforded 2-alkylamino-4,6-dialkoxynitrobenzene intermediate. The crude product may be used for further transformation without any purification or after purifying using silica gel column chromatography.

The nitro intermediate (2 mmol) obtained may be reduces to the amino compound employing general procedures H or I.

General Synthesis of Hetero Disubstituted Dialkoxy Ortho-Phenylenediamines: General Procedure J3

To a stirred solution of 3,5-difluorophenol (3 g; 17 mmol) in dichloromethane (30 mL) at 0° C., conc. HNO₃ (2.5 mL) is added dropwise over 10 min. The reaction mixture is then stirred at 0° C. for 60 min at which the nitration is complete as indicated by TLC. After the reaction is complete cold H₂O (30 mL) is added to the reaction flask and stirred. The contents are then poured into a separatory funnel and the layers removed. The aqueous layer is then extracted with EtOAc (2×30 mL) and the combined organic layers are dried over magnesium sulfate. After removal of the drying agent, the solvent is removed under vacuum to the crude product mixture is purified using silica gel column chromatography to provide the nitrodifluorophenol.

General Procedure J4

To a stirred solution of 3,5-difluoro-4-nitrophenol (4 mmol) in DMF (6 mL) at rt solid K₂CO₃ (8 mmol) is added. An alkyl halide or mesylate (prepared from the corresponding alcohol and methanesulfonyl chloride, see General Procedure P2) (4.4 mmol) is added to the reaction mixture and heated to 80° C. until the reaction is complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture is poured into EtOAc (40 ml) and washed with water (2×20 ml) and brine (30 ml). The organic layer is dried over magnesium sulfate and after removal of the drying agent, the solvent is removed under vacuum to afford the desired product. The crude product may be used for further transformation without any purification or after purifying using silica gel column chromatography.

General Procedure J5

To a stirred solution of 2,6-difluoro-4-alkoxynitrobenzene obtained above (3.0 mmol) and triethylamine (6.0 mmol) in DMF (6 mL), a solution of alkyl amine (3.0 mmol) in DMF (2 mL) is added dropwise at it within 15 min, and then stirred at rt for 5 h. The reaction mixture is treated with cold H₂O (10 mL), and extracted with EtOAc (2×15 mL), The combined organic layers is washed with H2O (10 mL) and brine (10 mL) and dried over sodium sulfate. After removal of the drying agent, the solvent is removed under high vacuum to afford the desired 2-alkylamino-4-alkoxy-6-fluoronitrobenzene. The crude product may be used for further transformation without any purification or after purifying using silica gel column chromatography.

General Procedure J6

To a stirred solution of 2-alkylamino-4-alkoxy-6-fluoronitrobenzene as obtained above (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of an alkoxide (2.2 mmol) in THF (may be generated by adding the corresponding alcohol to a 1M solution of KOBu^(t) in THF) is added dropwise and under the N₂ stream. The reaction mixture is maintained at 0° C. until the reaction is complete as indicated by TLC or HPLC. The reaction mixture is then treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers is washed with brine, and dried over sodium sulfate. Evaporation of the solvent in vacuo afforded the desired hetero dialkoxy substituted nitro intermediate. The crude product may be used for further transformation without any purification or after purifying using silica gel column chromatography.

General Procedure J7

The nitro intermediate (2 mmol) obtained above is dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until the reaction is complete as indicated by TLC or HPLC. The reaction mixture is then filtered through a celite pad to remove the catalyst. The solvent is removed under high vacuum to afford the desired hetero disubstituted dialkoxy ortho-phenylenediamine.

General Procedure for Synthesis of Benzimidazoles: General Procedure K

A solution of an ortho phenylenediamine (2 mmol) and an appropriate aryl aldehyde in ethanol is refluxed until the reaction is complete as indicated by TLC or HPLC. The solvent is removed in vacuo and the residue obtained is purified by silica gel column chromatography to afford the desired 2-arylbenzimidazole.

General Procedure for Synthesis of Monoalkoxyanilines: Method A: General Procedure L1

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of a potassium alkoxide (2.2 mmol) in THF (may be generated by adding the corresponding alcohol to a 1M solution of KOBu^(t) in THF) is added dropwise and under the N₂ stream. The reaction mixture is stirred at 0° C. until completion, as indicated by TLC or HPLC. The reaction mixture is then treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crude product could be used directly for further transformation without any purification, or after purifying using silica gel column chromatography.

Method B: General Procedure M1

To a stirred solution of 4-nitrophenol (2 mmol) in DMF (6 mL) at rt, solid potassium carbonate (4 mmol) is added. An alkyl halide or mesylate (prepared from the corresponding alcohol and methanesulfonyl chloride, see General Procedure P2) (2.2 mmol) is then added to the reaction mixture and heated to 80° C. until completion, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture is then treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crude product could be used directly for further transformation without any purification, or after purifying using silica gel column chromatography.

General Procedure for Synthesis of Homo Disubstituted Alkoxy-Anilines: Method C General Procedure N1

To a stirred solution of 2,4-difluoronitrobenzene (2.0 mmol) in anhydrous THF (4 mL) at 0° C., an alcohol (4.4 mmol) is added followed by powdered potassium t-butoxide (4.4 mmol) in one portion under a N₂ stream. The reaction mixture is then warmed to rt and heated under reflux until completion, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture is treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the 2,4-dialkoxynitrobenzene. The crude product could then be used for further transformation without any purification, or after purifying using silica gel column chromatography.

General Procedure for Synthesis of Alkoxy-Anilines: General Procedure O2

To a stirred solution of 4-alkoxy-2-fluoronitrobenzene obtained above (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of an alkoxide (2.2 mmol) in THF (may be generated by adding the corresponding alcohol to a 1M solution of potassium t-butoxide in THF) is added dropwise and under a N₂ stream. The reaction mixture is maintained at 0° C. until completion, as indicated by TLC or HPLC. The reaction mixture is then treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine, and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired hetero-substituted dilkoxynitrobenzene. The crude product may be used for further transformation without any purification or after purifying using silica gel column chromatography.

Method E: General Procedure P1

To a stirred solution of a 2-nitro-5-fluorophenol (2.0 mmol) in anhydrous THF (4 mL) at 0° C., an alcohol (2.2 mmol) is added followed by powdered potassium t-butoxide (4.2 mmol) in one portion under a N₂ stream. The reaction mixture is then warmed up to rt and heated under reflux until completion, as indicated by TLC or HPLC. After cooling to rt, the crude reaction mixture is treated with an alkyl halide or mesylate (2.2 mmol, prepared from the corresponding alcohol and methanesulfonyl chloride) and heated under reflux until completion, as indicated by TLC or HPLC. The reaction mixture is then cooled to rt, treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine, and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the hetero-substituted dilkoxynitrobenzene. The crude product may be used for further transformation without any purification or after purifying using silica gel column chromatography.

General Procedure P2

A primary or secondary alcohol (20 mmol, 1 eq) is dissolved in DCM (25 mL), TEA (40 mmol, 2 eq) is added and the mixture is cooled to 0° C. To this mixture, methanesulfonyl chloride (30 mmol, 1.5 eq) is added slowly with stirring and the reaction mixture is stirred at 0° C. for an hour and at rt for another hour (until the reaction is complete by HPLC). The solvent is removed and to this saturated aqueous sodium bicarbonate is added. The product is extracted with EtOAc (3×) and washed with sodium bicarbonate and water. The solvent is removed in vacuuo to afford the product methanesulfonate.

General Procedure for Synthesis of Alkyl Phenones; Method F: General Procedure Q1

To a stirred solution of 4′-hydroxyacetophenone (1.2 mmol) in DMF (10 mL) at rt, solid potassium carbonate (3.0 mmol) is added. An alkyl halide or mesylate (prepared from the corresponding alcohol and methanesulfonyl chloride, see General Procedure P2) (1.0 mmol) is added to the reaction mixture and heated to 80° C. until completion, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture is quenched by removing solvent in vacuuo and treating the residue with saturated sodium bicarbonate. The aqueous layer is poured into EtOAc (20 ml) and washed with H₂O (2×10 ml) and brine (15 ml). The organic layer is dried over magnesium sulfate, and the solvent is removed in vacuuo to afford the desired product. The crude alkylated product may be used for further transformation without any purification or after purifying using silica gel column chromatography.

Method G: General Procedure Q2

To a stirred solution of an alcohol (75 mmol) in DMSO (80 mL) at rt, solid cesium carbonate (150 mmol) is added. 4′-fluoro-alkylphenone (50 mmol) is added to the reaction mixture and heated to 90° C. until completion, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture is treated with saturated sodium bicarbonate (150 ml). The aqueous layer is extracted with diethyl ether (4×100 ml). The organic layer is washed with H₂O (2×10 ml) and brine (15 ml). The organic layer is dried over magnesium sulfate, and the solvent is removed in vacuuo to afford the desired alkoxy acetophenone. The crude alkylated acetophenone may be used for further transformation without any purification or after purifying using silica gel column chromatography.

General Procedure for N-Aryl Imidazoles: Method H: General Procedure R1

To a stirred solution of alkoxyacetophenone (2 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq.) is added. The reaction mixture is stirred under nitrogen at 0° C. for 1 h and is allowed to warm to ambient temperature until completion, as indicated by TLC or HPLC. The solvent is then removed in vacuuo and the crude alpha-bromoacetophenone is used for further transformation.

General Procedure R2

To a stirred solution of an alkoxy aniline (1.2 eq., 2 mmol) in anhydrous DMF (5 mL) diisopropylethylamine (3 eq. 6 mmol) is added, followed by a slow addition of the alpha-bromoacetophenone described above (1.6 mmol). The reaction mixture is stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture is then diluted with cold H₂O and the product is isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline is purified by chromatography (Silica gel). Pure product obtained from 2-4% MeOH/DCM (yield ˜50-60%).

General Procedure R3

To a stirred solution of alkylated aniline described above (2 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 6 mmol) is added, followed by a slow addition of an acid chloride or anhydride (3 eq., 6 mmol). The reaction mixture is stirred under nitrogen at 0° C. for 1 h and allowed to warm to ambient temperature until completion, as indicated by TLC or HPLC. The solvent is removed in vacuuo, and the crude amide is used for further transformation.

General Procedure R4

To a stirred solution of the amide described above (2 mmol) in AcOH (2 mL), ammonium acetate (excess, ˜20 eq.) is added. The reaction mixture is stirred at 90° C. overnight. The reaction mixture is then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which is purified by column chromatography (Silica gel). Pure product is obtained from 4-6% MeOH/DCM (yield 40-50%).

General Procedure S1

To a stirred solution of an alkoxy aniline (2 mmol) in DCM (4 mL) at rt, TEA (2.5 mmol) is added followed by an acid chloride or anhydride (2.5 mmol). The reaction mixture is stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture is treated with saturated aqueous sodium bicarbonate solution (5 mL), then extracted with EtOAc (2×15 mL). The combined organic layers were washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the anilide. The crude product is used for further transformation.

General Procedure S2

To a stirred solution of the anilide (2 mmol) obtained as above in anhydrous THF (4 mL) solid sodium hydride (60% dispersion in oil; 2.2 mmol) is added in portions. After the addition, a solution of a bromo-acetophenone (2.2 mmol) (prepared as described earlier) in anhydrous THF (2 mL) is added to the reaction mixture. The reaction is then allowed to proceed at rt or heated under reflux as needed. Upon completion of the reaction, EtOAc (20 mL) is added to the reaction mixture followed by H₂O (10 mL). The organic layer is washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the N-alkylated anilide. The crude product may be used for further transformation.

General Procedure S3

To a stirred solution of the N-alkylated anilide (1 mmol) obtained as above in AcOH (3 mL), solid NH₄OAc (20 mmol) is added in one portion. The reaction mixture is then heated to 100° C. overnight. The reaction mixture is cooled to rt, and treated with saturated aqueous sodium bicarbonate solution while stirring to until the pH is 7-8. The contents were extracted with EtOAc (2×15 mL). The combined organic layers is washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired N-aryl imidazole. The crude product is purified using silica gel column chromatography.

General Procedure T1

4N hydrogen chloride in dioxane solution (4 mmol) is added to a mixture of BOC-amino compound (1 mmol) in anhydrous DCM (5 mL), and the mixture is stirred at rt until complete. Evaporation of the solvents in vacuo afforded deprotected amine hydrochloride.

General Procedure T2

A benzyl alkyl ether, benzyl ester, or a benzyl phenyl ether is dissolved in MeOH and hydrogenated in the presence of 10% Pd/C catalyst until the reaction is complete. reaction mixture is then filtered through a celite pad to remove the catalyst. Evaporation of the solvent in vacuo afforded the alcohol, carboxylic acid, or phenol, respectively.

General Procedure T3

A phenol (0.2 mmol) in anhydrous DMF (5 mL) is alkylated by a bromide or a mesylate (0.3 mmol) at it (for a bromide, 60% NaH as base) or at 90° C. (for a mesylate, K₂CO₃ as base). The reaction is quenched by adding sat. NaHCO₃. The resulting mixture is extracted with EtOAc washed with brine and dried. The crude product is purified by silica gel column chromatography if desired.

Example 1 1-Butyl-2-(3-cyclohexylmethoxy-phenyl)-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole

Hydroxy benzimidazole was formed employing 1-BOC-4-[2-(4-amino-3-butylamino-phenoxy)-ethyl]-piperazine (synthesized via General Procedures G1 and G2 and H) (2.92 g; 10 mmol) and 3-hydroxybenzaldehyde (1.34 g, 11 mmol) in ethanol (20 mL) following the general procedure K. The crude product was purified by silica gel column chromatography using 2% MeOH in DCM (3.2 g).

MS m/z 396 (M+H)⁺

A solution of above mentioned hydroxybenzimidazole compound (39.4 mg, 0.1 mmol) in THF (2 ml) was added cyclohexylmethyl bromide (19.5 mg, 0.11 mmol) and NaH (0.8 mg, 60% , 0.12 mmol) at 0° C. The resulting reaction mixture was warmed to rt and stirred for additional 12 h. The mixture was quenched with brine and extracted into EtOAc (2×10 mL). Combined organic EtOAc extracts were dried over sodium sulfate and concentrated to give compound which was purified by silica gel column chromatography using dichloromethane and 2% methanol in dichloromethane as eluent, to give N—BOC compound, which was subjected to General Procedure T1 affording 1-butyl-2-(3-cyclohexylmethoxy-phenyl)-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole as a hydrochloride salt, 36.8 mg.

MS m/z 491 (M+H)⁺

Example 2 (3-(3-butyl-2-(3-, 5-di-tert-butyl-2-methoxy-phenyl)-3H-benzimidazol-5-yloxy-propyl)-diiethyl-amine

This compound was prepared according to the general procedure K by refluxing a mixture of 3,5-di-t-butyl-5-methoxybenzaldehyde (100 mg) and N²-Butyl-4-(3-diethylamino-propoxy)-benzene-1,2-diamine (synthesized via General Procedures G1 and G2 and H) (50 mg) in ethanol overnight. Ethanol was removed in vacuo and the residue was purified by silica gel chromatography using 5% MeOH in DCM to give (3-(3-butyl-2-(3-,5-di-tert-butyl-2-methoxy-phenyl)-3H-benzimidazol-5-yloxy-propyl)-diiethyl-amine (45.0 mg).

MS: m/z 522 (M+H)⁺

Example 3 (2-(3-butyl-2-(3-(4-tert-butyl-phenoxy)-phenyl)-3H-benzimidazol-5-yloxy-ethyl)-diisopropyl-amine

A solution of 2-(n-butylamino)-4-(2-diisopropylaminoethoxy)aniline (synthesized via General Procedures G1 and G2 and H) (61.4 mg, 0.2 mmol) and (3-(4-tert-butyl-phenoxy)-benzaldehyde (synthesized via General Procedure B) (56 mg, 0.22 mmol) in ethanol (2 mL) was condensed following General Procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford (2-(3-butyl-2-(3-(4-tert-butyl-phenoxy)-phenyl)-3H-benzimidazol-5-yloxy-ethyl)-diisopropyl-amine (54 mg).

MS m/z 542 (M+H)+

Example 4 (3-{4-[1-butyl-6-(4-tert-butyl-phenoxy)-1H-benzimidazol-2-yl]-phenoxy}-propyl)-diethyl-amine

To a stirred solution of 4-hydroxybenzaldehyde (20 mmol) in DMSO (80 mL) at rt, solid Cs₂CO₃ (50 mmol) was added. A mesylate (prepared from 3-diethylamino-1-propanol and methanesulfonyl chloride, General Procedure P2) (30 mmol) was added to the reaction mixture and heated to 90° C. until the reaction was complete as indicated by LC-MS (10 h). After cooling to rt, the reaction was quenched by cold H₂O (100 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with brine (3×50 mL) and dried (anhydrous Na₂SO₄). The solvent was removed in vacuo, and the crude product was purified by silica gel column chromatography, eluting with 10% MeOH in DCM+0.5% Et₃N, giving the desired 4-(3-diethylaminopropoxy)benzaldehyde.

A solution of 2-t-butylamino-4-(4-n-butylphenoxy)aniline (synthesized via General Procedures G1 and G2 and H) (130 mg, 0.4 mmol) and 4-(3-diethylaminopropoxy)benzaldehyde obtained above (70 mg, 0.3 mmol) in MeOH (10 mL) was subjected to General Procedure K. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with 10% MeOH in DCM with a gradual increment of Et₃N (0.5 to 1%), affording the desired benzimidazole (120 mg).

MS m/z 528 (M+H)⁺

¹H NMR (400 MHz, CDCl₃): δ 0.84 (t, 3H), 1.05 (t, 6H), 1.24 (m, 2H), 1.31 (s, 9H), 1.75 (m, 2H), 1.98 (m, 2H), 2.58 (q, 4H), 2.66 (t, 2H), 4.09 (t, 2H), 4.13 (t, 2H), 6.93 (d, 2H,), 7.00 (dd, 1H), 7.02 (d, 2H), 7.07 (d, 1H), 7.33 (d, 2H,), 7.62 (d, 2H), 7.72 (d, 1H) ppm.

Example 5 1-butyl-6-(4-tert-butyl-phenoxy)-2-[3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzimidazole

To a stirred solution of 3-hydroxybenzaldehyde (20 mmol) in DMSO (50 mL) at rt, solid Cs₂CO₃ (60 mmol) was added. 1-(2-chloroethyl)pyrrolidine hydrochloride (30 mmol) was added to the reaction mixture and heated to 90° C. for 9 h. After cooling to rt, the reaction was quenched by cold H₂O (50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with brine (3×50 mL) and dried (anhydrous Na₂SO₄). The solvent was removed in vacuo to afford crude 3-(2-pyrrolidin-1-yl-ethoxy)benzaldehyde.

A solution of 2-t-butylamino-4-(4-n-butylphenoxy)aniline (synthesized via General Procedures G1 and G2 and H) (130 mg, 0.4 mmol) and 3-(2-pyrrolidin-1-yl-ethoxy)benzaldehyde obtained above (70 mg, -0.3 mmol) in MeOH (10 mL) was subjected to General Procedure K. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with 10% MeOH in DCM with a gradual increment of Et₃N (0.5 to 1%), to afford the desired benzimidazole (100 mg).

MS m/z 512 (M+H)⁺

¹H NMR (400 MHz, CDCl₃): δ0.83 (t, 3H), 1.22 (m, 2H), 1.29 (s, 9H), 1.74 (m, 2H), 1.87 (m, 4H), 2.78 (m, 4H), 3.03 (m, 2H), 4.16 (t, 2H), 4.25 (m, 2H), 6.94 (d, 2H), 7.01 (br d, 1H), 7.07 (m, 2H), 7.26 (m, 2H), 7.33 (d, 2H), 7.41 (t, 1H), 7.74 (d, 1H) ppm.

The following Examples were synthesized according to the Methods employed for Examples 1-5;

Exam- ple Name 6 1-butyl-6-(4-tert-butyl-phenoxy)-2-[2-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-1H-benzimidazole 7 1-butyl-2-[3-(naphthalen-2-yloxy)-phenyl]-6-(2-piperazin-1-yl- ethoxy)-1H-benzoimidazole 8 2-biphenyl-4-yl-1-butyl-6-(2-piperazin-1-yl-ethoxy)-1H- benzimidazole 9 1-butyl-6-(4-tert-butyl-phenoxy)-2-[4-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-1H-benzimidazole 10 1-butyl-2-[3-(3,3-dimethyl-butoxy)-phenyl]-6-(2-piperazin-1-yl- ethoxy)-1H-benzoimidazole 11 1-butyl-6-(4-fluoro-3-trifluoromethyl-phenoxy)-2-[4-(2- pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzimidazole 12 1-butyl-2-(3-phenoxy-phenyl)-6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 13 1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(2-piperidin-1-yl- ethoxy)-1H-benzimidazole 14 1-butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-6-(2-piperidin-1-yl- ethoxy)-1H-benzimidazole 15 1-butyl-6-[2-(4-chloro-phenyl)-ethoxy]-2-[4-(2-pyrrolidin-1- yl-ethoxy)-phenyl]-1H-benzimidazole 16 1-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(2-piperidin-1-yl- ethoxy)-1H-benzimidazole 17 1-butyl-2-(4-tert-butyl-phenyl)-6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 18 dibutyl-{4-[1-butyl-6-(3-diethylamino-propoxy)-1H- benzimidazol-2-yl]-phenyl}-amine 19 (2-{3-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-3H- benzoimidazol-5-yloxy}-ethyl)-diisopropyl-amine 20 {3-[3-butyl-2-(4-tert-butyl-phenyl)-3H-benzimidazol- 5-yloxy]-propyl}-diethyl-amine 21 1-butyl-2-(3,5-di-tert-butyl-2-methoxy-phenyl)-6-(2-piperazin-1- ylethoxy)-1H-benzoimidazole 22 {3-[3-butyl-2-(3-{4-[2-(4-methoxy-phenyl)-ethoxy]-phenyl}- propyl)-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 23 1-butyl-2-naphthalen-2-yl-6-(2-piperazin-1-yl-ethoxy)-1H- benzimidazole 24 (2-{3-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-3H- benzoimidazol-5-yloxy}-ethyl)-dimethyl-amine 25 2-benzofuran-2-yl-1-butyl-6-(2-piperazin-1-yl-ethoxy)-1H- benzimidazole 26 1-butyl-6-(2-piperazin-1-yl-ethoxy)-2-[3-(3-trifluoromethyl- phenoxy)-phenyl]-1H-benzimidazole 27 2-benzhydryl-1-butyl-6-(2-piperazin-1-yl-ethoxy)-1H- benzimidazole 28 1-Butyl-2-(4-chloro-phenyl)-6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 29 {3-[3-Butyl-2-(4-isopropoxy-phenyl)-3H-benzoimidazol-5- yloxy]-propyl}-diethyl-amine 30 1-Butyl-6-(2-piperazin-1-yl-ethoxy)-2-[3-(4,4,4-trifluoro- butoxy)-phenyl]-1H-benzoimidazole

Example 31 (2-(3-butyl-2-(2,4,4-trimethylpentyl)-3H-benzimidazol-5-yloxy-propyl)-diethyl-amine

A solution of 2-(n-butylamino)-4-(3-diethylaminopropoxy)aniline (synthesized via General Procedures G1 and G2 and H) (58.6 mg, 0.2 mmol) and 3,5,5-trimethylhexanal (31.2 mg, 0.22 mmol) in ethanol (2 mL) was subjected to General Procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford (2-(3-butyl-2-(2,4,4-trimethylpentyl)-3H-benzimidazol-5-yloxy-propyl)-diethyl-amine (41.0 mg).

MS m/z 416 (M+H)⁺

Example 32 1-[(5-pyrrolidin-1-yl)pentyl-6-(3-diethylaminopropoxy)-2-piperidin-3-yl-1H-benzimidazole

A solution of 1-(t-butyloxycarbonyl)piperidine-3-carboxaldehyde (235 mg; 1.1 mmol) and 2-[(5-pyrrolidin-1-yl)pentylamino]-4-(3-diethylaminopropoxy)-4-(2-diethylaminoethoxy)aniline (synthesized via General Procedures G1 and G2 and H) (362 mg; 1 mmol) in ethanol (5 mL) was subjected to General Procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford 410 mg of tert-butyl 3-{[1-(5-pyrrolidin-1-yl)pentyl]-6-(3-diethylaminopropoxy)-1H-benzimidazol-2-yl}piperidine-1-carboxylate.

A solution of tert-butyl 3-{[1-(5-pyrrolidin-1-yl)pentyl]-6-(3-diethylaminopropoxy)-1H-benzimidazol-2-yl}piperidine-1-carboxylate (271 mg; 0.5 mmol) in DCM (2 mL) was subjected to General Procedure T1. The resulting mixture was stirred for 4-5 h and the solvent was removed in vacuo. The residue obtained was washed with ether twice and dried under vacuum to afford 1-[(5-pyrrolidin-1-yl)pentyl-6-(3-diethylaminopropoxy)-2-piperidin-3-yl-1H-benzimidazole trihydrochloride (210 mg).

MS m/z 442 (M+H)⁺

Example 33 1-[(5-pyrrolidin-1-yl)pentyl-6-(3-diethylaminopropoxy)-2-piperidin-4-yl-1H-benzimidazole

A solution of 1-(t-butyloxycarbonyl)piperidine-4-carboxaldehyde (235 mg; 1.1 mmol) and 2-[(5-pyrrolidin-1-yl)pentylamino]-4-(3-diethylaminopropoxy)-4-(2-diethylaminoethoxy)aniline (362 mg; 1 mmol) in ethanol (5 mL) was subjected to General Procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford 430 mg of tert-butyl 4-{[1-(5-pyrrolidin-1-yl)pentyl]-6-(3-diethylaminopropoxy)-1H-benzimidazol-2-yl}piperidine-1-carboxylate.

A solution of tert-butyl 4-{[1-(5-pyrrolidin-1-yl)pentyl]-6-(3-diethylaminopropoxy)-1H-benzimidazol-2-yl}piperidine-1-carboxylate (271 mg; 0.5 mmol) in DCM (2 mL) was subjected to General Procedure T1. The resulting mixture was stirred for 4-5 h and the solvent was removed in vacuo. The residue obtained was washed with ether twice and dried under vacuum to afford 1-[(5-pyrrolidin-1-yl)pentyl-6-(3-diethylaminopropoxy)-2-piperidin-4-yl-1H-benzimidazole trihydrochloride (220 mg).

MS m/z 442 (M+H)⁺

Example 34 {1-butyl-[4,6-di(3-diethylaminopropoxy)]-2-piperidin-4-yl}-1H-benzimidazole

A solution of 1-(t-butyloxycarbonyl)piperidine-4-carboxaldehyde (235 mg; 1.1 mmol) and 2-butylamino-4,6-di(3-diethylaminopropoxy)aniline (synthesized via General Procedures J1 and J2 and I) (424 mg; 1 mmol) in ethanol (5 mL) was subjected to General Procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford 425 mg of tert-butyl {4-[1-butyl-4,6-di(3-diethylaminopropoxy)-1H-benzimidazol-2-yl]}piperidine-1-carboxylate.

A solution of tert-butyl 4-[1-butyl-4,6-di(3-diethylaminopropoxy)-1H-benzimidazol-2-yl]piperidine-1-carboxylate (308 mg; 0.5 mmol) in DCM (2 mL) was subjected to General Procedure T1. The resulting mixture was stirred for 4-5 h and the solvent was removed in vacuo. The residue obtained was washed with ether twice and dried under vacuum to afford {1-butyl-[4,6-di(3-diethylaminopropoxy)]-2-piperidin-4-yl}-1H-benzimidazole trihydrochloride (260 mg).

MS m/z 516 (M+H)⁺

Example 35 (3-(3-butyl-2-(3-(4-tert-butyl-phenoxy)-phenyl)-7-(2-pyrrolidin-1-yl-ethoxy)-3H-benzimidazol-5-yloxy-propyl)-diiethyl-amine

Example 35 was formed employing 3-(4-t-butyl-phenoxy)benzaldehyde (synthesized via General Procedure B) (50 mg; 0.20 mmol) and 2-butylamino-4-(3-diethylaminopropoxy)-6-(2-pyrrolidin-1-yl-ethoxy)aniline (synthesized via General Procedures J3-J7) (39 mg; 0.20 mmol) in ethanol (1 mL) according to General Procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford 40 mg of Example 243.

MS m/z 641 (M+H)⁺

Example 36 1-butyl-2-{4-[2-(4-chlorophenyl)ethoxy]-phenyl}-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazole

This compound was prepared according to the General Procedure K by refluxing a mixture of 4-[2-(4-chloro-phenyl)-ethoxy]-bezaldehyde (synthesized via General Procedure A) (100 mg) and N²-Butyl-4-(2-pyrrolidin-1-ylethoxy)-benzene-1,2-diamine (synthesized via General Procedures G1 and G2 and H) (50 mg) in ethanol overnight. Ethanol was removed in vacuo and the residue was purified by silica gel chromatography using 5% MeOH in DCM to give pure 1-butyl-2-{4-[2-(4-chlorophenyl)ethoxy]-phenyl}-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazole (37.0 mg, 40%).

MS: m/z 518 (M+H)⁺

Example 37 1-butyl-2-{3-[3-tert-butyl-phenoxy]-phenyl}-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole

A mixture of 1-BOC-4-[2-(4-amino-3-butylamino-phenoxy)-ethyl]-piperazine (synthesized via General Procedures G1 and G2 and H) (0.130 g, 0.512 mmol) and 3-(3-tert-butylphenoxy)benzaldehyde was subjected to General Procedure K. Reaction was concentrated and purified on silica gel chromatography using DCM-2% MeOH/DCM. The BOC-group was removed employing General Procedure T1 to give 1-butyl-2-{3-[3-tert-butyl-phenoxy]-phenyl}-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole (0.10 g).

MS (m/z): 527 (M+H)⁺

Example 38 1-butyl-2-{3-[biphenyl-4-yloxy]-phenyl}-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole

A mixture of 3-bromobenzaldehyde (1.05 g) and 1-BOC-4-[2-(4-amino-3-butylamino-phenoxy)-ethyl]-piperazine (1.85 g) was subjected to General Procedure K. The ethanol was removed in vacuo and the residue purified on silica gel using 1-2% MeOH/DCM.

To a solution of the aryl bromide (0.07 mmol) in pyridine (1 mL) was added copper powder (0.14 mmol) followed by K₂CO₃ (0.35 mmol) and the respective substituted phenol (0.14 mmol). The mixture was heated at 110° C. overnight, then diluted with water (2 mL) and extracted with EtOAc (3×2 mL). The combined organic extract was dried over Na₂SO₄, filtered and concentrated to an oil, which was purified by column chromatography on silica gel. The pure product was obtained from 1-6% methanol/DCM (yield 28-42%). The BOC-group was removed via General Procedure T1 to give 1-butyl-2-{3-[biphenyl-4-yloxy]-phenyl}-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole.

MS (m/z): 547 (M+H)⁺

Example 39 1-butyl-2-{4-[2-(4-chlorophenyl)ethoxy]phenyl}-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole

A mixture of 4-[2-(4-chloro-phenyl)-ethoxy]-benzaldehyde (0.08 g) and 1-BOC-4-[2-(4-amino-3-butylamino-phenoxy)-ethyl]-piperazine (0.10 g) was subjected to General Procedure K. Ethanol was removed in vacuo and the residue purified on silica gel with 1-2% MeOH/DCM. The BOC-group was removed employing General Procedure T1 to give 1-butyl-2-{4-[2-(4-chlorophenyl)ethoxy]-phenyl}-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole (0.081 g).

MS (m/z): 533 (M+H)⁺

The following Examples were synthesized according to the Methods employed for Examples 35-39;

Example Name 40 [3-(3-butyl-2-{3-[2-(4-chloro-phenyl)-ethoxy]-4-nitro-phenyl}-3H- benzimidazol-5-yloxy)-propyl]-diethyl-amine 41 [2-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H- benzimidazol-5-yloxy)-ethyl]-diethyl-amine 42 1-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(piperidin-4-ylmethoxy)- 1H-benzoimidazole 43 1-butyl-2-{3-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-piperazin-1-yl- ethoxy)-1H-benzoimidazole 44 {3-[3-butyl-2-(2-{4-[2-(4-chlorophenyl)-ethoxy]-phenyl}-ethyl)-3H- benzimidazol-5-yloxy]-propyl}-diethyl-amine 45 1-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H- benzimidazole 46 1-butyl-6-[2-(4-butyl-piperazin-1-yl)-ethoxy]-2-[3-(3-trifluoromethyl- phenoxy)-phenyl]-1H-benzimidazole 47 {3-[3-butyl-2-(2-{4-[2-(4-chlorophenyl)-ethoxy]-phenyl}-ethyl)-3H- benzimidazol-5-yloxy]-propyl}-diethyl-amine 48 (3-{3-butyl-2-[3-(4-methoxy-phenoxy)-phenyl]-3H-benzimidazol-5- yloxy}-propyl)-diethyl-amine 49 {3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-diethylamino- ethoxy)-benzimidazol-1-yl]-propyl}-diethyl-amine 50 [3-(1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-1H-benzimidazol- 4-yloxy)-propyl]-diethyl-amine 51 [3-(1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-1H-benzimidazol- 5-yl)-propyl]-diethyl-amine 52 1-butyl-2-[3-(2-isopropyl-phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 53 {3-[3-butyl-2-(2-{4-[3-(4-methoxy-phenyl)-propoxy]-phenyl}-ethyl)-3H- benzimidazol-5-yloxy]-propyl}-diethyl-amine 54 {3-[3-butyl-2-(2-{4-[4-(4-methoxy-phenyl)-butoxy]-phenyl}-ethyl)-3H- benzimidazol-5-yloxy]-propyl}-diethyl-amine 55 [3-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-3-ethoxy-phenyl}-3H- benzimidazol-5-yloxy)-propyl]-diethyl-amine 56 (3-{3-butyl-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-3H-benzimidazol- 5-yloxy}-propyl)-diethyl-amine 57 1-butyl-2-[3-(4-chloro-phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)- 1H-benzoimidazole 58 1-butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 59 1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(piperidin-4-yloxy)- 1H-benzoimidazole 60 3-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H- benzoimidazol-5-yloxy)-1-aza-bicyclo[2.2.2]octane 61 1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2,2,6,6,- tetramethyl-piperidin-4-yloxy)-1H-benzoimidazole 62 2-[3-(4-butoxy-phenoxy)-phenyl]-1-butyl-6-(2-piperazin-1-yl-ethoxy)- 1H-benzoimidazole 63 [3-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H- benzimidazol-5-yloxy)-propyl]-diethyl-amine 64 {3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3-(3-methyl-butyl)-3H- benzimidazol-5-yloxy]-propyl}-diethyl-amine 65 [3-(2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3-hexyl-3H-benzimidazol- 5-yloxy)-propyl]-diethyl-amine 66 {3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-diethylamino- ethoxy)-benzimidazol-1-yl]-propyl}-dimethyl-amine 67 1-butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-6-(2-piperazin-1- ylethoxy)-1H-benzoimidazole 68 [3-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H- benzimidazol-5-yloxy)-propyl]-diethyl-amine 69 {3-[2-(4-benzyloxy-3,5-dimethyl-phenyl)-3-butyl-3H-benzimidazol-5- yloxy]-propyl}-diethyl-amine 70 {3-[3-butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-3H-benzimidazol-5- yloxy]-propyl}-diethyl-amine 71 1-butyl-6-[2-(4-methyl-piperazin-1-yl)-ethoxy]-2-[3-(3-trifluoromethyl- phenoxy)-phenyl]-1H-benzimidazole 72 1-butyl-6-[2-(4-isopropyl-piperazin-1-yl)-ethoxy]-2-[3-(3- trifluoromethyl-phenoxy)-phenyl]-1H-benzoimidazole 73 1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(3-piperazin-1-yl- propoxy)-1H-benzoimidazole 74 (3-{3-butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-3H-benzimidazol-5- yloxy}-propyl)-diethyl-amine 75 1-butyl-2-[3-(3,4-dimethoxy-phenoxy)-phenyl]-6-(2-piperidin-4-yloxy)- 1H-benzoimidazole 76 1-butyl-2-[3-(4-chloro-benzyloxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)- 1H-benzoimidazole 77 1-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 78 (3-{2-[2-(4-benzyloxy-phenyl)-ethyl]-3-butyl-3H-benzimidazol-5-yloxy}- propyl)-diethyl-amine 79 (3-{3-butyl-2-[2-(4-phenethyloxy-phenyl)-ethyl]-3H-benzimidazol-5- yloxy}-propyl)-diethyl-amine 80 {3-[3-butyl-2-(2-{4-[2-(4-fluoro-phenyl)-ethoxy]-phenyl}-ethyl)-3H- benzimidazol-5-yloxy]-propyl}-diethyl-amine 81 [3-(3-butyl-2-{2-[4-(4-chloro-benzyloxy)-phenyl]-ethyl}-3H- benzimidazol-5-yloxy)-propyl]-diethyl-amine 82 (3-{3-butyl-2-[4-(4-fluoro-benzyloxy)-phenyl]-3H-benzimidazol-5- yloxy}-propyl)-diethyl-amine 83 {3-[2-(3-benzyloxy-phenyl)-3-butyl-3H-benzimidazol-5-yloxy]-propyl}- diethyl-amine 84 [3-(3-butyl-2-{4-chloro-3-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H- benzimidazol-5-yloxy)-propyl]-diethyl-amine 85 1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)- 1H-benzimidazole 86 1-butyl-2-[4-(4-isopropyl-phenoxy)-phenyl]-6-(2-piperazin-1-yl- ethoxy)-1H-benzoimidazole 87 1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-[3-(4-methyl- piperazin-1-yl)-propoxy]-1H-benzoimidazole 88 1-butyl-6-[2-(4-butyl-piperazin-1-yl)-ethoxy]-2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-1H-benzoimidazole 89 1-butyl-2-[3-(3,4-dimethoxy-phenoxy)-phenyl]-6-(2-piperazin-1-yl- ethoxy)-1H-benzoimidazole 90 1-butyl-2-[4-(4-tert-butyl-benzyl)-phenyl]-6-(2-piperazin-1-yl-ethoxy)- 1H-benzoimidazole 91 N-{4-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-2-[2- (4-chloro-phenyl)-ethoxy]-phenyl}-2,2-dimethyl-propioinamide 92 (3-{3-butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-3H- benzimidazol-5-yloxy}-propyl)-diethyl-amine 93 1-butyl-2-[4-(naphthalen-2-yloxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)- 1H-benzoimidazole 94 1-butyl-2-[3-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-6-(2- piperazin-1-yl-ethoxy)-1H-benzoimidazole 95 [3-(3-butyl-2-{4-[2-(4-methoxy-phenyl)-ethoxy]-phenyl}-3H- benzimidazol-5-yloxy)-propyl]-diethyl-amine 96 4-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-2-[2-(4- chloro-phenyl)-ethoxy]-phenylamine 97 1-{4-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-2-[2- (4-chloro-phenyl)-ethoxy]-phenyl}-3-isopropyl-urea 98 {3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-dimethylamino- ethoxy)-benzimidazol-1-yl]-propyl}-dimethyl-amine 99 1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-[2-(4-methyl-piperazin-1- yl)-ethoxy]-1H-benzimidazole 100 1-butyl-6-(4-cyclopentyl-phenoxy)-2-[4-(4-methyl-piperazin-1- ylmethyl)-phenyl]-1H-benzoimidazole 101 {3-[2-(4-benzyloxy-phenyl)-3-cyclopentylmethyl-3H-benzimidazol-5- yloxy]-propyl}-diethyl-amine 102 1-butyl-6-(4-butyl-phenoxy)-2-{3,5-dimethyl-4-[2-(1-methyl-pyrrolidin- 2-yl)-ethoxy]-phenyl}-1H-benzoimidazole 103 1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(3-pyrrolidin-1-yl- propoxy)-1H-benzoimidazole 104 {3-[2-(4-benzyloxy-phenyl)-3-isobutyl-3H-benzimidazol-5-yloxy]- propyl}-diethyl-amine 105 [3-(3-butyl-2-{3-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H- benzimidazol-5-yloxy)-propyl]-diethyl-amine 106 1-butyl-6-(1-butyl-piperidin-4-yloxy)-2-[3-(3,5-dichloro-phenoxy)- phenyl]-1H-benzoimidazole 107 1-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(1-ethyl-piperidin-4-yloxy)-1H- benzoimidazole 108 1-butyl-6-(4-fluoro-3-trifluoromethyl-phenoxy)-2-[4-(4-methyl-piperazin-1- ylmethyl)-phenyl]-1H-benzoimidazole 109 diethyl-{3-[3-isobutyl-2-(2-{4-[2-(4-methoxy-phenyl)-ethoxy]-phenyl}- ethyl)-3H-benzimidazol-5-yloxy]-propyl}-amine 110 {3-[2-(2-{4-[2-(4-chlorophenyl)-ethoxy]-phenyl}-ethyl)-3-isobutyl-3H- benzimidazol-5-yloxy]-propyl}-diethyl-amine 111 1-butyl-6-(2-piperazin-1-yl-ethoxy)-2-[3-(3-trifluoromethyl-phenoxy)- phenyl]-1H-benzimidazole 112 1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(2-pyrrolidin-1-yl-ethoxy)- 1H-benzimidazole 113 1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-[2-(4-methyl- piperazin-1-yl)-ethoxy]-1H-benzimidazole 114 {3-[2-(4-benzyloxy-phenyl)-3-cyclopentyl-3H-benzimidazol-5-yloxy)- propyl]-diethyl-amine 115 1-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-5-(4-methyl- piperazin-1-ylmethyl)-1H-benzoimidazole 116 [2-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H- benzimidazol-5-yloxy)-ethyl]-dimethyl-amine 117 [2-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H- benzimidazol-5-yloxy)-ethyl]-diisopropyl-amine 118 1-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-[2-(4-methyl-piperazin- 1-yl)-ethoxy]-1H-benzimidazole 119 (3-{1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-1H-benzimidazol-4- yloxy}-propyl)-diethyl-amine 120 2-(3-butoxy-phenyl)-1-butyl-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole 121 1-butyl-2-[3-(4-methanesulfonyl-benzyloxy)-phenyl]-6-(2-piperazin-1- yl-ethoxy)-1H-benzoimidazole 122 4′{3-[1-butyl-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]- phenoxy}-biphenyl-4-carbonitrile 123 {3-[2-(4-benzyloxy-phenyl)-3-butyl-3H-benzimidazol-5-yloxy]-propyl}- diethyl-amine 124 1-Butyl-2-[4-(3-chloro-phenoxy)-phenyl]-6-(2-pyrrolidin-1-yl-ethoxy)- 1H-benzoimidazole 125 1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-[2-(4-isopropyl- piperazin-1-yl)-ethoxy]-1H-benzoimidazole 126 {3-[2-(3-benzyloxy-4-methoxy-phenyl)-3-butyl-3H-benzimidazol-5- yloxy)-propyl]-diethyl-amine 127 (3-{3-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-3H-benzimidazol-5- yloxy}-propyl)-diethyl-amine 128 {3-[3-butyl-2-(3-phenoxy-phenyl)-3H-benzimidazol-5-yloxy]-propyl}- diethyl-amine 129 1-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-[2-(4-ethyl-piperazin-1- yl)-ethoxy]-1H-benzimidazole 130 1-butyl-2-[4-(2,3-di-methoxy-phenoxy)-phenyl]-6-(2-piperazin-1- ylethoxy)-1H-benzoimidazole 131 [3-(3-butyl-2-{2-[4-(4-chloro-benzyloxy)-phenyl]-ethyl}-3H- benzimidazol-5-yloxy)-propyl]-diethyl-amine 132 (3-{3-butyl-2-[3-(4-chloro-phenoxy)-phenyl]-3H-benzimidazol-5-yloxy}- propyl)-diethyl-amine 133 {3-[2-(4-benzyloxy-phenyl)-3-isopropyl-3H-benzimidazol-5-yloxy]- propyl}-diethyl-amine 134 (2-{3-butyl-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-3H- benzoimidazol-5-yloxy}-ethyl)-diisopropyl-amine 135 1-butyl-6-[2-(4-ethyl-piperazin-1-yl)-ethoxy]-2-[3-(3-trifluoromethyl- phenoxy)-phenyl]-1H-benzimidazole 136 {3-[3-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-3H-benzimidazol-5- yloxy]-propyl}-diethyl-amine 137 (3-{2-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-3H-benzimidazol-5- yloxy}-ethyl)-cyclohexyl-methyl-amine 138 1-butyl-6-[2-(4-propyl-piperazin-1-yl)-ethoxy]-2-[3-(3-trifluoromethyl- phenoxy)-phenyl]-1H-benzimidazole 139 1-butyl-6-(4-butyl-phenoxy)-2-[4-(4-methyl-piperazin-1-ylmethyl)- phenyl]-1H-benzoimidazole 140 1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(2-morpholin-4-yl- ethoxy)-1H-benzimidazole 141 4-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-2- phenethyloxy-phenylamine 142 {2-[2-(4-benzyloxy-phenyl)-3-phenethyl-3H-benzimidazol-5-yloxy]- ethyl}-diethyl-amine 143 {3-[3-butyl-2-(4-phenoxy-phenyl)-3H-benzimidazol-5-yloxy]-propyl}- diethyl-amine 144 3-[4-(2-{3-butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-3H-benzimidazol- 5-yloxy}-ethyl)-piperazin-1-yl]-propan-1-ol 145 1-butyl-6-(2-pyrrolidin-1-yl-ethoxy)-2-[3-(3-trifluoromethyl-phenoxy)- phenyl]-1H-benzimidazole 146 {2-[2-[4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-diethylamino- ethoxy)-benzimidazol-1-yl]-ethyl}-dimethyl-amine 147 1-butyl-6-(2-morpholin-4-yl-ethoxy)-2-[3-(3-trifluoromethyl-phenoxy)- phenyl]-1H-benzimidazole 148 1-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(1-methyl-piperidin-4- yloxy)-1H-benzoimidazole 149 N′-[3-butyl-2-(2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-ethyl)-3H- benzimidazol-5-yl]-N,N-diethyl-propane-1,3-diamine 150 1-butyl-2-[3-(2,4-dichloro-phenoxy)-phenyl]-6-(2-pyrrolidin-1-yl- ethoxy)-1H-benzimidazole 151 1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-morpholin-4-yl- ethoxy)-1H-benzimidazole 152 1-butyl-6-(2-piperazin-1-yl-ethoxy)-2-[4-(4-trifluoromethyl-phenoxy)- phenyl]-1H-benzoimidazole 153 2-[4-(biphenyl-4-yloxy)-phenyl]-1-butyl-6-(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 154 1-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(2-morpholin-4-yl- ethoxy)-1H-benzimidazole 155 1-butyl-2-[3-(3,4-dimethoxy-phenoxy)-phenyl]-6-(2-piperazin-1-yl- ethoxy)-1H-benzoimidazole 156 1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-5-(1H-imidazol-4- ylmethoxy)-1H-benzoimidazole 157 {3-[2-(2-benzyloxy-phenyl)-3-butyl-3H-benzimidazol-5-yloxy]-propyl}- diethyl-amine 158 {3-[1-Butyl-6-(3-diethylamino-propoxy)-2-piperidin-4-yl-1H- benzoimidazol-4-yloxy]-propyl}-diethyl-amine 159 (2-{2-[2-(4-Benzyloxy-phenyl)-ethyl]-3-phenethyl-3H-benzoimidazol- 5-yloxy}-ethyl)-diethyl-amine 160 [3-(3-Butyl-2-{3-[4-(4-fluoro-benzyloxy)-phenyl]-propyl}-3H- benzoimidazol-5-yloxy)-propyl]-diethyl-amine 161 [3-(4-Benzyloxy-phenyl)-propyl]-[1-butyl-6-(3-diethylamino-propoxy)- 1H-benzoimidazol-2-yl]-amine 162 {3-[3-Butyl-2-(3-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-propyl)-3H- benzoimidazol-5-yloxy]-propyl}-diethyl-amine 163 1-Butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(2-imidazol-1-yl-ethoxy)-1H- benzoimidazole 164 1-[4-(2-{3-Butyl-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-3H- benzoimidazol-5-yloxy}-ethyl)-piperazin-1-yl]-ethanone 165 N-[3-Butyl-2-(2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-ethyl)-3H- benzoimidazol-5-yl]-N-(3-diethylamino-propyl)-N′,N′-diethyl-propane- 1,3-diamine

Example 166 (3-(1-Butyl-2-{4-[2-(4-chlorophenyl)-ethoxy]-phenyl}-6-(3-diethylaminopropoxy)-1H-benzimidazole-4-yloxy)-propyl)diethyl-amine

This compound was prepared according to General Procedure K by refluxing a mixture of 4-[2-(4-chloro-phenyl)-ethoxy]-bezaldehyde (300 mg) and N¹-Butyl-3,5-bis-(3-diethylamino-propoxy)-benzene-1,2-diamine (synthesized via General Procedures J1 and J2 and I) (200 mg) in ethanol overnight. Ethanol was removed in vacuo and the residue was purified by silica gel chromatography using 5% MeOH in DCM to give pure (3-(1-Butyl-2-{4-[2-(4-chlorophenyl)-ethoxy]-phenyl}-6-(3-diethylaminopropoxy)-1H-benzimidazole-4-yloxy)-propyl)diethyl-amine (100 mg).

MS: m/z 663 (M+H)⁺

Example 167 {3-[1-Butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(3-diethylaminopropoxy)-1H-benzimidazole-4-yloxy]-propyl}diethyl-amine

{3-[1-Butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(3-diethylaminopropoxy)-1H-benzimidazole-4-yloxy]-propyl}diethyl-amine was formed employing 3(4-t-butyl-phenoxy)benzaldehyde (127 mg; 0.50 mmol) and 2-butylamino-4,6-di(3-diethylaminopropoxy)aniline (synthesized via General Procedures J1 and J2 and I) (1.6 mg; 0.25 mmol) in ethanol (1 mL) following General Procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford 145 mg (76%) of {3-[1-Butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(3-diethylaminopropoxy)-1H-benzimidazole-4-yloxy]-propyl}diethyl-amine.

MS: m/z 657 (M+H)⁺

Example 168 {3-[2-(2-[4-(2-(4-chloro-phenyl)-ethoxy])-phenyl]-ethyl)-6-(3-diethylaminopropoxy)-3H-benzimidazole-4-yloxy]-propyl}diethyl-amine

This compound was prepared according to the General Procedure K by refluxing a mixture of 3-{4-[2-(4-chloro-phenyl)-ethoxy]-propionaldehyde (100 mg) and 3,5-Bis-(3-diethylamino-propxy)-benzene-1,2-diamine (synthesized via General Procedures J1 and J2 and I) (50 mg) in ethanol overnight. Ethanol was removed in vacuo and the residue was purified by silica gel chromatography using 10% MeOH in DCM to give {3-[2-(2-[4-[2-(4-chloro-phenyl)-ethoxy])-phenyl]ethyl)-6-(3-diethylaminopropoxy)-3H-benzimidazole-4-yloxy]-propyl}diethyl-amine (30 mg).

MS: m/z 635 (M+H)⁺

Example 169 (3-(1-Butyl-6-(3-diethylaminopropoxy)-2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-1H-benzimidazole-4-yloxy)-propyl)diethyl-amine

4-(4-Chloro-3-trifluoromethyl)phenoxybenzaldehyde (synthesized employing General Procedure B) (150 mg) and 2-butylamino-4,6-di(3-diethylaminopropoxy)aniline (synthesized via General Procedures J1 and J2 and 1) 106 mg; 0.25 mmol) in ethanol (1 mL) were condensed employing General Procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford 160 mg of (3-(1-Butyl-6-(3-diethylaminopropoxy)-2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-1H-benzimidazole-4-yloxy)-propyl)diethyl-amine.

MS: m/z 703 (M+H)⁺

Example 170 (3-(1-Butyl-6-(3-diethylaminopropoxy)-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-benzimidazole-4-yloxy)-propyl)diethyl-amine

A solution of 2-butylamino-4,6-di(3-diethylaminopropoxy)aniline (synthesized via General Procedures J1 and J2 and I) (84.4 mg, 0.2 mmol) and 4-(4-fluoro-3-trifluoromethyl)phenoxybenzaldehyde (synthesized employing General Procedure B) (62.5 mg, 0.2 mmol) in ethanol (2 mL) was heated to reflux following the General Procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford 3-(1-Butyl-6-(3-diethylaminopropoxy)-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-benzimidazole-4-yloxy)-propyl)diethyl-amine (62 mg).

MS m/z 687 (M+H)

The following Examples were synthesized according to the Methods employed for Examples 166-170;

Example Name 171 {3-[2-[3-(3,5-Dichloro-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}-diethyl-amine 172 1-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-4,6-bis-(2-pyrrolidin- 1-yl-ethoxy)-1H-benzoimidazole 173 {3-[2-[3-(3,4-Dichloro-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)- 1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 174 (3-{6-(3-diethylamino-propoxy)-2-[3-(3-trifluoromethyl-phenoxy)- phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 175 {3-[1-Butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 176 {3-[2-[3-(4-Chloro-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}-diethyl-amine 177 {3-[1-Butyl-2-[3-(4-chloro-phenoxy)-phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 178 {3-[1-Butyl-6-(3-diethylamino-propoxy)-2-(3-p-tolyloxy-phenyl)-1H- benzoimidazol-4-yloxy]-propyl}-diethyl-amine 179 {3-[1-Butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 180 1-Butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazole 181 {3-[3-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-7-(2-pyrrolidin-1- yl-ethoxy)-3H-benzoimidazol-5-yloxy]-propyl}-diethyl-amine 182 (3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(3-fluoro-phenoxy)- phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 183 {3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(3-diethylamino- propoxy)-1-isopropyl-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 184 {3-[1-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-pyrrolidin-1- yl-ethoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 185 2-{4-[1-butyl-4,6-bis-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl- phenoxy}-benzoic acid methyl ester 186 {3-[2-[4-(biphenyl-4-yloxy)-phenyl]-1-butyl-6-(3-diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}-diethyl-amine 187 {3-[2-[4-(3,5-Bis-trifluoromethyl-phenoxy)-phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 188 {3-[1-butyl-2-[4-(4-chloro-benzylsulfanyl)-phenyl]-6-(3-diethylamino- propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 189 {3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(3-diethylamino- propoxy)-3H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 190 (3-{1-butyl-6-(3-diethylamino-propoxy)-2-[3-(3-trifluoromethyl- phenoxy)-phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 191 [3-(1-butyl-6-(3-diethylamino-propoxy)-2-{4-[2-(4-fluoro-phenyl)- ethoxy]-phenyl}-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 192 (3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(3-trifluoromethyl- phenoxy)-phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 193 {3-[2-[3-(4-tert-Butyl-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)- 1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 194 (3-{1-Butyl-6-(3-diethylamino-propoxy)-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2- trifluoromethyl-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine 195 {3-[1-Butyl-2-[4-chloro-2-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]- 6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 196 2-[3-(4-Chloro-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 197 1-Butyl-2-[3-(4-chloro-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazole 198 {3-[3-butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-7-(2- pyrrolidin-1-yl-ethoxy)-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 199 {2-[1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(2-diisopropylamino- ethoxy)-1H-benzimidazol-4-yloxy]-ethyl}-diethyl-amine 200 {3-[2-[4-(3,5-Bis-trifluoromethyl-phenoxy)-phenyl]-1-butyl-6-(3- diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl- amine 201 {3-[2-[4-(3,5-Bis-trifluoromethyl-phenoxy)-phenyl]-1-butyl-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 202 (3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(4-methoxy-phenoxy)- phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 203 1-Butyl-2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-4,6-bis-(2- pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 204 2-{4-[2-(4-Chloro-phenyl)-ethoxy]-phenyl}-4,6-bis-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazole 205 1-Butyl-2-[4-(4-tert-butyl-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazole 206 1-Butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-4,6-bis-(2- pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 207 {3-[1-Butyl-2-[4-(3-chloro-phenoxy)-phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 208 2-[5,7-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazol-2-yl]-5-[2-(4- chloro-phenyl)-ethoxy]-phenol 209 2-[3-(4-tert-butyl-phenoxy)-phenyl]-4,6-bis-(2-pyrrolodin-1-yl-ethoxy)- 1H-benzimidazole 210 (3-{6-(3-Diethylamino-propoxy)-2-[2-(1,1-difluoro-ethyl)-4-(4-fluoro-3- trifluoromethyl-phenoxy)-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)- diethyl-amine 211 {3-[1-Butyl-2-[4-(4-tert-butyl-phenoxy)-phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 212 2-[4-(4-tert-Butyl-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)- 1H-benzoimidazole 213 {3-[1-Butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 214 [3-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6- diethylaminomethyl-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine 215 (3-{6-(3-Diethylamino-propoxy)-2-[4-(4-fluoro-3-trifluoromethyl- phenoxy)-phenyl]-1H-benzoimidazol-4-yloxyl}-propyl)-diethyl-amine 216 (3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(4-trifluoromethyl- pyrimidin-2-ylsulfanyl)-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)- diethyl-amine 217 {3-[6-(3-Diethylamino-propoxy)-2-(3-p-tolyloxy-phenyl)-1H- benzoimidazol-4-yloxy]-propyl}-diethyl-amine 218 4-{3-[1-Butyl-4,6-bis-(3-diethylamino-propoxy)-1H-benzoimidazol-2- yl]-phenoxy}-benzonitrile 219 [3-(3-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-7-pyrrolidin-1-yl- 3H-benzoimidazol-5-yloxy)-propyl]-diethyl-amine 220 {3-[1-butyl-2-[4-(4-chloro-phenylmethanesulfinyl)-phenyl]-6-(3- diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl- amine 221 (3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(naphthalen-2-yloxy)- phenyl]-1H-benzoimidazole-4-yloxy}-propyl)-diethyl-amine 222 (3-{6-(3-diethylamino-propoxy)-2-[4-(3-trifluoromethyl-phenoxy)- phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 223 (3-{1-butyl-6-(3-diethylamino-propoxy)-2-[3-(4-methoxy-phenoxy)- phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 224 2-[3-(3,4-Dichloro-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)- 1H-benzoimidazole 225 {3-[2-[4-(4-tert-Butyl-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)- 1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 226 {3-[3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-7-[2-(tetrahydro- furan-2-yl)-ethoxy]-3H-benzimidazol-5-yloxy}-propyl)-diethyl-amine 227 1-Butyl-2-[4-(3-chloro-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazole 228 [3-(7-Butoxy-3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H- benzoimidazol-5-yloxy)-propyl]-diethyl-amine 229 4-{3-[4,6-Bis-(3-diethylamino-propoxy)-1H-benzoimidazol-2-yl]- phenoxy}-benzonitrile 230 2-[3-(3,5-Dichloro-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)- 1H-benzoimidazole 231 {3-[1-butyl-2-(2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-ethyl)-6-(3- diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl- amine 232 {3-[1-butyl-6-(3-diethylamino-propoxy)-2-(3-phenoxy-phenyl)-1H- benzimidazol-4-yloxy]-propyl}-diethyl-amine 233 {3-[1-Butyl-2-[2-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-6-(3- diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl- amine 234 2-[4-(4-Chloro-3-trifluoromethyl-phenoxy)-phenyl]-4,6-bis-(2- pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 235 {3-[1-Butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-6-(2- pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl- amine 236 [3-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-methyl-3H- benzimidazol-5-yloxy)-propyl]-diethyl-amine 237 {3-[1-butyl-6-(3-diethylamino-propoxy)-2-(4-phenoxy-phenyl)-1H- benzimidazol-4-yloxy]-propyl}-diethyl-amine 238 5-[4,6-bis-(3-diethylamino-propoxy)-1H-benzoimidazlo-2-yl]-2-[2-(4-chloro- phenyl)-ethoxy]-phenol 239 [3-(6-Butoxy-1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-1H- benzoimidazol-4-yloxy)-propyl]-diethyl-amine 240 {3-[2-[4-Chloro-2-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-6-(3- diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl- amine 241 1-butyl-4-(4-chloro-benzyloxy)-2-{4-[2-(4-chloro-phenyl)-ethoxy]- phenyl}-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazole 242 4-{4-[1-butyl-4,6-bis-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]- phenoxy}-benzonitrile 243 [3-(1-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-fluoro-1H- benzoimidazol-4-yloxy)-propyl]-diethyl-amine 244 (3-{6-(3-diethylamino-propoxy)-2-[3-(4-methoxy-phenoxy)-phenyl]-1H- benzimidazol-4-yloxy}-propyl)-diethyl-amine 245 (3-{6-(3-diethylamino-propoxy)-2-[4-(4-methoxy-phenoxy)-phenyl]-1H- benzimidazol-4-yloxy}-propyl)-diethyl-amine 246 {3-[1-butyl-2-[4-(4-chloro-3-fluoro-phenoxy)-phenyl]-6-(3- diethylamino-propoxy)-1H-benzimidazol-4-yl]-propyl}-diethyl-amine 247 (3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(quinolin-8-yloxy)-phenyl]- 1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 248 {3-[2-[2-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-6-(3- diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl- amine 249 2-[{2-[1-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2- morpholin-4-yl-ethoxy)-1H-benzoimidazol-4-yloxy]-ethyl}-(2-chloro- ethyl)-amino]-ethanol 250 (3-{6-(3-Diethylamino-propoxy)-2-[3-(4-fluoro-3-trifluoromethyl- phenoxy)-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine 251 [3-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-7-isopropoxy-3H- benzimidazol-5-yloxy)-propyl]-diethyl-amine 252 [3-(1-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6- cyclopentylmethoxy-1H-benzoimidazol-4-yloxy)-propyl]-diethyl-amine 253 1-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-4,6-bis-(2- morpholin-4-yl-ethoxy)-1H-benzoimidazole 254 {3-[2-[4-[2-(4-Chloro-phenyl)-ethoxy]-3-(3-diethylamino-propoxy)-phenyl]- 6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine

Example 255 {3-[2-[1-butyl-6-(4-tert-butyl-phenoxy)-1H-benzimidazol-2-yl}-5-(3-diethylamino-propoxy)-phenoxy]propyl}-diethyl-amine

To a stirred solution of 2,4-dihydroxybenzaldehyde (10 mmol) in DMSO (50 mL) at rt, solid Cs₂CO₃ (45 mmol) was added. A mesylate (prepared from 3-diethylamino-1-propanol and methanesulfonyl chloride, General Procedure P2) (25 mmol) was added to the reaction mixture and heated to 90° C. until the reaction was complete as indicated by LC-MS (˜10 h). After cooling to rt, the reaction was quenched by cold H₂O (100 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with brine (3×50 mL) and dried (anhydrous Na₂SO₄). The solvent was removed in vacuo to afford the desired 2,4-bis(3-diethylaminopropoxy)benzaldehyde which was used for further transformation.

To a stirred solution of 2,4-difluoronitrobenzene (50 mmol), Et₃N (100 mmol) and DMF (80 mL) was added dropwise a solution of n-butylamine (51 mmol) in DMF (20 mL) at rt, and the mixture was stirred at rt for 5 h. The reaction was quenched by cold H₂O (100 mL), and the resulting mixture was extracted with EtOAc (4×100 mL). The combined EtOAc extracts were washed with brine (3×60 mL) and dried (anhydrous Na₂SO₄). The solvent was removed in vacuo to afford the desired 2-n-butylamino-4-fluoronitrobenzene which was used for further transformation.

A mixture of 2-n-butylamino-4-fluoronitrobenzene (10 mmol), 4-t-butylphenol (13 mmol), solid K₂CO₃ (30 mmol) and DMF (30 mL) was heated with stirring at 90° C. for 10 h. The reaction was quenched by cold H₂O (50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with brine (2×50 mL) and dried (anhydrous Na₂SO₄). The solvent was removed in vacuo, and the crude products were purified by silica gel column chromatography (eluting with 10% EtOAc in hexane), giving 2-n-butylamino-4-(4-t-butylphenoxy)nitrobenzene.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (50 mg) until completion as indicated by LC-MS (˜4 h). The reaction mixture was then filtered through a celite pad to remove the catalyst. The MeOH solution containing 2-n-butylamino-4-(4-t-butylphenoxy)aniline was used directly for further transformation.

A solution of 2-n-butylamino-4-(4-t-butylphenoxy)aniline (130 mg, 0.4 mmol) and 2,4-bis(3-diethylaminopropoxy)benzaldehyde obtained above (110 mg, 0.3 mmol) in MeOH (10 mL) was refluxed until the reaction was complete. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with 10% MeOH in DCM with a gradual increment of Et₃N (0.5 to 1%), to afford the desired benzimidazole (100 mg).

MS m/z 657 (M+H)⁺

¹H NMR (400 MHz, CDCl₃) of HCl salt of the benzimidazole: δ 0.80 (t, 3H), 1.19 (m, 2H), 1.26 (t, 6H), 1.32 (s, 9H), 1.41 (t, 6H), 1.74 (m, 2H), 2.44 (m, 4H), 3.12-3.39 (m, 12H), 4.21 (t, 2H), 4.29 (m, 4H), 6.68 (br d, 1H), 6.79 (br s, 1H), 6.98 (d, 2H), 7.17 (d, 1H), 7.22 (dd, 1H), 7.35 (d, 1H), 7.40 (d, 2H), 8.06 (d, 1H), 11.4 (br, N.HCl), 11.9 (br, N.HCl) ppm.

Example 256 (3-{2-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethylamine

A solution of 2-(3-diethylaminopropoxy)-4-[2-(4-chlorophenyl)ethoxy]benzaldehyde (synthesized via General Procedures D1 and D2) (429 mg; 1.1 mmol) and 2-(n-butylamino)-4-(3-diethylaminopropoxy)aniline (synthesized via General Procedures G1 and G2 and I) (293 mg; 1 mmol) in ethanol (5 mL) was heated to reflux following General Procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford of (3-{2-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethylamine (430 mg).

MS m/z 663 (M+H)⁺

Example 257 (3-{1-butyl-6-(4-tert-butyl-phenoxy)-2-[4-(3-diethylamino-propoxy)-phenyl]-1H-benzimidazol-4-yloxy}propyl)-diethyl-amine

To a stirred solution of 4-hydroxybenzaldehyde (20 mmol) in DMSO (80 mL) at rt, solid Cs₂CO₃ (50 mmol) was added. The mesylate prepared from 3-diethylamino-1-propanol and methanesulfonyl chloride, General Procedure P2 (30 mmol) was added to the reaction mixture and heated to 90° C. until the reaction was complete. After cooling to rt, the reaction was quenched by cold H₂O (100 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with brine (3×50 mL) and dried (anhydrous Na₂SO₄). The solvent was removed in vacuo, and the crude product was purified by silica gel column chromatography (eluting with 10% MeOH in DCM+0.5% Et₃N) to afford 4-(3-diethylaminopropoxy)benzaldehyde.

To a stirred solution of 6-(3-diethylaminopropoxy)-2,4-difluoronitrobenzene (11 mmol) and triethylamine (22 mmol) in DMF (20 mL), a solution of n-butylamine (11 mmol) in DMF (8 mL) was added dropwise at rt, and the mixture was stirred at rt for 10 h. The reaction was quenched by cold H₂O (50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with brine (3×50 mL) and dried (anhydrous Na₂SO₄). The solvent was removed in vacuo to afford the desired 2-n-butylamino-6-(3-diethylaminopropoxy)-4-fluoronitrobenzene which was used for further transformation.

A mixture of 2-n-butylamino-6-(3-diethylaminopropoxy)-4-fluoronitrobenzene obtained above (3 mmol), 4-t-butylphenol (4 mmol), solid K₂CO₃ (9 mmol) and DMF (15 mL) was heated with stirring at 90° C. for 15 h. The reaction was quenched by cold H₂O (30 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with brine (2×50 mL) and dried (anhydrous Na₂SO₄). The solvent was removed in vacuo, and the crude products were purified by silica gel column chromatography (eluting with 10% MeOH in DCM), giving 2-n-butylamino-4-(4-t-butylphenoxy)-6-(3-diethylaminopropoxy)nitrobenzene.

The nitro intermediate (1 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (40 mg) until completion as indicated by LC-MS (˜4 h). The reaction mixture was then filtered to remove the catalyst. The MeOH solution containing 2-n-butylamino-4-(4-t-butylphenoxy)-6-(3-diethylaminopropoxy)aniline was used directly for further transformation.

A solution of 2-n-butylamino-4-(4-t-butylphenoxy)-6-(3-diethylaminopropoxy)-aniline (90 mg, 0.2 mmol) and 4-(3-diethylaminopropoxy)benzaldehyde obtained above (65 mg, 0.25 mmol) in MeOH (10 mL) was refluxed until the reaction was complete as indicated by LC-MS (˜10 h). The solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with 10% MeOH in DCM with a gradual increment of Et₃N (0.5 to 1%), to afford the desired benzimidazole (80 mg).

MS m/z 657 (M+H)⁺

¹H NMR (400 MHz, CDCl₃) of HCl salt of the benzimidazole: δ 0.80 (t, 3H), 1.21 (m, 2H), 1.31 (s, 9H), 1.40 (m, 12H), 1.74 (m, 2H), 2.39 (m, 2H), 2.52 (m, 2H), 3.17-3.27 (m, 12H), 3.80 (m, 2H), 4.18 (m, 4H), 6.60 (br s, 1H), 6.62 (br s, 1H), 6.95 (d, 2H), 7.14 (br, 2H), 7.39 (d, 1H), 7.80 (br, 2H), 11.17 (br, N.HCl), 11.83 (br, N.HCl) ppm.

Example 258 2-{2,4-bis-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-1-butyl-6-(4-tert-butyl-phenoxy)-1H-benzimidazole

A solution of 2-n-butylamino-4-(4-t-butylphenoxy)aniline (synthesized via General Procedures J3-J7) (100 mg, 0.3 mmol) and 2,4-bis[2-(1-methyl-2-pyrrolidin-2-yl)-ethoxy]benzaldehyde (synthesized via General Procedure C) (55 mg, 0.15 mmol) in MeOH (10 mL) was subjected to General Procedure K. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with 10% MeOH in DCM with a gradual increment of Et₃N (0.5 to 1%), to afford the desired benzimidazole (50 mg).

MS m/z 653 (M+H)⁺

¹H NMR (400 MHz, CDCl₃): δ 0.73 (t, 3H), 1.10-2.53 (m, 22H), 1.32 (s, 9H), 2.20 (s, 3H), 2.39 (s, 3H), 3.94-3.99 (m, 6H), 6.50 (m, 2H), 6.92 (d, 2H), 6.98 (m, 1H), 7.05 (d, 1H), 7.32 (d, 2H), 7.42 (d, 1H), 7.70 (d, 1H) ppm.

Example 259 2-[2,4-bis-(2-pyrrolidin-1-yl)-ethoxy]phenyl}-1-butyl-6-(4-butyl-phenoxy)-1H-benzimidazole

A solution of 2-n-butylamino-4-(4-n-butylphenoxy)aniline (synthesized via General Procedures G1 and G2 and I) (80 mg, 0.25 mmol) and 2,4-bis(2-pyrrolidin-1-yl-ethoxy)benzaldehyde (synthesized via General Procedure C) (50 mg, 0.15 mmol) was subjected to General procedure K. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with 10% MeOH in DCM with a gradual increment of Et₃N (0.5 to 1%), to afford the desired benzimidazole (80 mg).

MS m/z 625 (M+H)⁺

¹H NMR (400 MHz, CDCl₃): δ0.73 (t, 3H), 0.92 (t, 3H), 1.10 (m, 2H), 1.35 (m, 2H), 1.55-1.60 (m, 4H), 1.64 (m, 4H), 1.83 (m, 4H), 2.39 (m, 4H), 2.58 (t, 2H), 2.65 (m, 4H), 2.73 (t, 2H), 2.93 (t, 2H), 3.96 (t, 2H), 4.07 (t, 2H), 4.16 (t, 2H), 6.60 (br s, 1H), 6.62 (dd, 1H), 6.92 (d, 2H), 6.96 (dd, 1H), 7.04 (d, 1H), 7.12 (d, 2H), 7.40 (d, 1H), 7.70 (d, 1H) ppm.

The following Examples were synthesized according to the Methods employed for Examples 255-259;

Example Name 260 1-butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-pyrrolodin-1-yl-ethoxy)- phenyl]-6-(2-pyrrolodin-1-yl-ethoxy)-1H-benzoimidazole 261 {3-[2-{1-butyl-6-[2-(4-chloro-phenyl)-ethoxy]-1H-benzimidazol-2-yl]-5-(3- diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine 262 2-{2,4-bis-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-1-butyl-6-(4-butyl- phenoxy)-1H-benzoimidazole 263 {3-{2-[1-butyl-5-(4-tert-butyl-phenoxy)-1H-benzimidazol-1-yl]-5-(3- diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine 264 1-Butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazole 265 2-[2,4-bis-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1-butyl-6-(4-cyclopentyl- phenoxy)-1H-benzoimidazole 266 2-{2,4-bis-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-1-butyl-6-(4- cyclopentyl-phenoxy)-1H-benzoimidazole 267 {3-[2-[1-butyl-6-(4-iospropyl-phenoxy)-1H-benzimidazol-2-yl]-5-(3- diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine 268 (2-{1-butyl-6-(2-dimethylamino-ethylsulfanyl)-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H- benzoimidazol-4-ylsulfanyl}-ethyl)-dimethyl-amine 269 2-[2,4-bis-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1-butyl-6-(4-tert-butyl- phenoxy)-1H-benzimidazole 270 {3-[2-[1-butyl-6-(4-butyl-phenoxy)-1H-benzimidazol-2-yl]-5-(3- diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine 271 {3-[2-[1-butyl-6-(4-fluoro-3-trifluoromethyl-phenoxy)-1H-benzimidazol-2- yl]-5-(3-diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine 272 2-[2,4-bis-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1-butyl-6-(4-isopropyl- phenoxy)-1H-benzoimidazole 273 1-Butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazole 274 (3-{3-Butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl- ethoxy)-phenyl]-3H-benzoimidazol-5-yloxy}-propyl)-diethyl-amine 275 {3-[2-[1-butyl-6-(4-cyclopentyl-phenoxy)-1H-benzimidazol-2-yl]-5-(3- diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine 276 {3-[2-[1-butyl-4-(4-tert-butyl-phenoxy)-1H-benzimidazol-2-yl]-5-(3- diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine 277 2-{2,4-bis-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-1-butyl-6-(4- isopropyl-phenoxy)-1H-benzoimidazole 278 (3-{5-[2-(4-chloro-phenyl)-ethoxy]-2-[6-(3-diethylamino-propoxy)-1- isopropyl-1H-benzimidazol-2-yl]-phenoxy}-propyl)-diethyl-amine 279 1-Butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl- ethoxy)-phenyl]-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 280 1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-4,6-bis-(1-methyl- piperidin-4-yloxy)-1H-benzimidazole 281 {3-[2-[6-(4-tert-butyl-phenoxy)-1H-benzimidazol-2-yl]-5-(3-diethylamino- propoxy)-phenoxy]-propyl}-diethyl-amine 282 1-butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-4,6-bis-(1-methyl-pyrrolidin-2- ylmethoxy)-1H-benzoimidazole 283 (3-{3-butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-diethylamino-ethoxy)- phenyl]-3H-benzimidazol-5-yloxy}-propyl)-diethyl-amine 284 (3-{2-[1-Butyl-6-(2-imidazol-1-yl-ethoxy)-1H-benzoimidazol-2-yl]-5-[2-(4- chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine 285 (3-{2-[1-Butyl-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]-5-[2-(4- chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine 286 {3-[2-(3,5-bis-benzyloxy-phenyl)-3-butyl-3H-benzimidazol-5-yloxy]- propyl}-diethyl-amine 287 4,6-bis-(2-azepan-1-yl-ethoxy)-1-butyl-2-[3-(4-tert-butyl-phenoxy)- phenyl]-1H-benzoimidazole 288 1-butyl-2-[3-(4-butyl-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)- 1H-benzoimidazole 289 1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-4,6-bis-(1-methyl-pyrrolidin-2- ylmethoxy)-1H-benzoimidazole 290 (2-{1-butyl-6-(2-dimethylamino-ethylsulfanyl)-2-[3-(3-trifluoromethyl- phenoxy)-phenyl]-1H-benzoimidazole-4-ylsufanyl}-ethyl)-dimethyl-amine 291 (3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(4-isopropyl-phenoxy)- phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 292 4,6-bis-(2-azepan-1-yl-ethoxy)-1-butyl-2-[3-(3,5-dichlorophenoxy)- phenyl]-1H-benzoimidazole 293 1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-4,6-bis-[2-(cyclohexyl-methyl- amino)-ethoxy]-1H-benzoimidazole 294 {3-[1-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(2-imidazol-1-yl-ethoxy)- 1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 295 [3-(2-{3,4-bis-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3-butyl-3H- benzimidazol-5-yloxy)-propyl]-diethyl-amine 296 1-butyl-4,6-bis-(1-methyl-piperidin-4-yloxy)-2-[3-(3-trifluoromethyl- phenoxy)-phenyl]-1H-benzoimidazole 297 4,6-bis-(2-azepan-1-yl-ethoxy)-1-butyl-2-[3-(3-trifluoromethyl-phenoxy)- phenyl]-1H-benzoimidazole 298 1-butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-4,6-bis-(1-ethyl-pyrrolidin-2- ylmethoxy)-1H-benzoimidazole 299 [3-(2-{2-benzyloxy-4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3-butyl-3H- benzimidazol-5-yloxy]-propyl}-diethyl-amine 300 {3-[2-[1-Butyl-6-(3-diethylamino-propoxy)-1H-benzoimidazol-2-yl]-5-(4- fluoro-3-trifluoromethyl-phenoxy)-phenoxy]-propyl}-diethyl-amine 301 {3-[2-[1-Butyl-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]-5-(4- fluoro-3-trifluoromethyl-phenoxy)-phenoxy]-propyl}-diethyl-amine 302 1-butyl-2-[3-(3,4-dimethoxy-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl- ethoxy)-1H-benzimidazole 303 (2-{1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-dimethylamino- ethylsulfanyl)-1H-benzoimidazol-4-ylsulfanyl}-ethyl)-dimethyl-amine 304 1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-4,6-bis-(1-ethyl-pyrrolidin-3- yloxy)-1H-benzoimidazole 305 {3-[2-[3-(3,4-bis-benzyloxy-phenyl)-3-butyl-3H-benzimidazol-5-yloxy]- propyl}-diethyl-amine 306 (3-{5-[2-(4-chloro-phenyl)-ethoxy]-2-[6-(3-diethylamino-propoxy)-1H- benzimidazol-2-yl]-phenoxy}-propyl)-diethyl-amine 307 1-butyl-2-[4-(2-diethylamino-ethoxy)-phenyl]-4,6-bis-[2-(methyl-phenyl- amino)-ethoxy]-1H-benzimidazole 308 {3-[3-butyl-2-{4-[2-(4-chlorophenyl)-ethoxy]-phenyl}-7-(pyridin-3-yloxy)- 3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 309 {2-[1-butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-6-(2-diisopropylamino- ethoxy)-1H-benzimidazol-4-yloxy]-ethyl}-diethyl-amine 310 {3-[3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-7-(pyridin-3- ylmethoxy)-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 311 2-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzoimidazlo-2-yl]-5-[2-(4- chloro-phenyl)-ethoxy]-phenol 312 {3-[3-butyl-2-[2-(4-chloro-phenylsulfanyl)-phenyl]-7-(3-diethylamino- propoxy)-3H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 313 (3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(4-fluoro-2-methoxy- phenoxy)-phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 314 [3-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-2-isopropoxy-phenyl}-3H- benzimidazol-5-yloxy)-propyl]-diethyl-amine 315 {2-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzoimidazlo-2-yl]-5-[2-(4- chloro-phenyl)-ethoxy]-phenoxy}-acetic acid methyl ester 316 (3-{2-[1-butyl-6-(4-tert-butyl-phenoxy)-1H-benzimidazol-2-yl]-5-[2-(4- chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine 317 (3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(2-isopropoxy-phenoxy)- phenyl]-1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine 318 (3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(2,3-dimethoxy-phenoxy)- phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 319 (3-{3-Butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-3H-benzoimidazol-5-yloxy}-propyl)-diethyl-amine 320 (2-{1-butyl-6-fluoro-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-1H- benzoimidazole-4-ylsufanyl}-ethyl)-dimethyl-amine 321 Methanesulfonic acid 5-[2-(4-chloro-phenyl)-ethoxy]-2-[6-(3-diethylamino- propoxy)-1H-benzoimidazol-2-yl]-phenyl ester 322 5-[2-(4-Chloro-phenyl)-ethoxy]-2-[6-(3-diethylamino-propoxy)-1H- benzoimidazol-2-yl]-phenol 323 {3-[1-butyl-6-(3-diethylamino-propoxy)-2-(4-pyrrolidin-1-yl-phenyl)-1H- benzoimidazol-4-yloxy]-propyl}-diethyl-amine 324 1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-4,6-bis-(1-methyl-piperidin-4- yloxy)-1H-benzimidazole 325 1-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-4,6-bis-(2-imidazol-1-yl- ethoxy)-1H-benzoimidazole 326 [2-(1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-fluoro-1H- benzoimidazol-4-ylsulfanyl)-ethyl]-dimethyl-amine

Example 327 {3-[1-Butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-(pyrrolidin-1-yl-ethoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine

4-[2-(4-chloro-phenyl)-ethoxy]-[2-(2-pyrrolidin-1-yl-ethoxy]-benzaldehyde (synthesized via General Procedures D1 and D2) (0.030 g, 0.080 mM) and N-butyl-3,5-bis(3-dimethylamino-propoxy)benzene-1,2-diamine (0.035 g, 0.080 mM) were subjected to General Procedure K. After removal of ethanol, the residue was purified on silica gel using 10% MeOH/DCM with 0.1-0.4% Et₃N, yield 0.025 g.

LC/MS (m/z): 776 (M+H)⁺

Example 328 1-Butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazole

A solution of 2-butylamino-4,6-bis(2-pyrrolidinyl-1-ethoxy)aniline (synthesized via General Procedures G1 and G2 and H) (78.4 mg, 0.2 mmol) and 2-pyrrolidin-1-yl-ethoxy-4-(4-fluoro-3-trifluoromethyl)phenoxybenzaldehyde (synthesized via General Procedure E) (91 mg, 0.22 mmol) was subjected to General Procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford Example 328 (62 mg).

MS m/z 768 (M+H)⁺.

Example 329 1-Butyl-2-[4-(4-Chloro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazole

A solution of 2-butylamino-4,6-bis(2-pyrrolidinyl-1-ethoxy)aniline (synthesized via General Procedures G1 and G2 and H) (78.4 mg, 0.2 mmol) and 2-pyrrolidin-1-yl-ethoxy-4-(4-chloro-3-trifluoromethyl)phenoxybenzaldehyde (synthesized via General Procedure E) (91 mg, 0.22 mmol) in ethanol (2 mL) was subjected to General Procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford Example 329 (62.5 mg)

MS m/z 784 (M+H)⁺

Example 330 (3-{2-[1-butyl-6-(3-diethylamino-propoxy)-4-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine

A solution of 2-(3-diethylaminopropoxy)-4-[2-(4-chlorophenyl)ethoxy]benzaldehyde (synthesized via General Procedure E) (858; 2.2 mmol) and 2-(n-butylamino)-4-(N,N-diethylaminopropoxy)-6-(N-pyrrolidineethoxy)aniline (synthesized via General Procedures J3-J7) (816 mg; 2 mmol) in ethanol (5 mL) was subjected to General Procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford 520 mg (34%) of Example 330.

MS m/z 776 (M+H)⁺

Example 331 (3-{2-[1-butyl-4,6-bis-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine

To a stirred solution of 2-(4-chlorophenyl)ethanol (20.0 mL, 148 mmol), TEA (31.0 mL, 222 mmol) in anhydrous DCM (100 mL) was added dropwise MsCl (12.0 mL, 156 mmol) at 0° C. within 8 min, and stirred at the same temperature for 2 h. The resulting yellow suspension was diluted with DCM (200 mL), washed with cold H₂O and brine, and dried. Removal of the solvent afforded the mesylate (33.0 g).

A mixture of the mesylate obtained as above (23.6 g, 100 mmol), 2,4-dihydroxybenzaldehyde (16.6 g, 120 mmol) and KHCO₃ (12.0 g, 120 mmol) in anhydrous DMF (150 mL) was heated at 130° C. for 4 h following the general procedure described for disubstitued benzaldehydes. The crude products were purified by flash chromatography (eluting with 10% EtOAc in hexanes), giving 4-(4-chlorophenyl)ethoxysalicylaldehyde (12.5 g) as a white solid.

Methanesulfonyl chloride, General Procedure P2 (2.90 mL, 37.5 mmol) was added dropwise at 0° C. to a stirred solution of 3-diethylaminopropanol (5.75 mL, 38.8 mmol), TEA (7.0 mL, 50.0 mmol) in anhydrous DCM (25 mL), and the mixture was stirred at the same temperature for 1 h, and at rt for an additional 1 h. After the removal of the solvent in vacuo, the solid residue was mixed with the aldehyde formed above (7.0 g, 25.0 mmol), Cs₂CO₃ (20.4 g, 62.5 mmol) and anhydrous DMSO (100 mL), and the whole mixture was heated at 90° C. for 6 h. following the general procedure described for disubstitued benzaldehydes to obtain oily 2-(3-diethylaminopropoxy)-4-[2-(4-chlorophenyl)ethoxy]benzaldehyde (11.0 g, ˜100% yield), which solidified upon standing.

To a stirred solution of 2,4,6-trifluoronitrobenzene (5.31 g, 30 mmol), TEA (8.37 mL, 60 mmol) and DMF (50 mL) was added dropwise a solution of n-butylamine (2.96 mL, 30 mmol) in DMF (20 mL) at rt following General Procedure G1 to obtain crude 2-butylamino-4,6-difluoronitrobenzene (9.0 g). This product was mixed with 3-diethylaminopropanol (11.1 mL, 75 mmol) and anhydrous THF (150 mL), and then powdered KOBu^(t) (8.5 g, 75 mmol) was added following General Procedure G2 to afford crude 2-butylamino-4,6-di(3-diethylaminopropoxy)nitrobenzene (15.5 g).

The nitro compound formed above (6.8 g, 15 mmol) dissolved in MeOH (90 mL) was hydrogenated following general procedure H and 2-butylamino-4,6-di(3-diethylaminopropoxy)aniline obtained was used directly for the next step.

Example 331 was formed employing phenylenediamine formed above (848 mg; 2 mmol) and 2-(3-diethylaminopropoxy)-4-[2-(4-chlorophenyl)ethoxy]benzaldehyde (858; 2.2 mmol) in ethanol (5 mL) following the general procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) to afford 400 mg of Example 331.

MS m/z 792 (M+H)⁺

Example 332 (3-{2-[1-Butyl-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine

2-butylamino-4,6-difluoronitrobenzene (9.0 g) was mixed with 1-pyrrolidineethanol (8.81 mL, 75 mmol) and anhydrous THF (150 mL), and then powdered KOBu^(t) (8.5 g, 75 mmol) was added following general procedures G1 and G2 described for homo disubstitued phenylenediamine to afford crude 2-butylamino-4,6-di(pyrrolidineethoxy)nitrobenzene (13.5 g).

The nitro compound formed above (6.3 g, 15 mmol) dissolved in MeOH (90 mL) was hydrogenated following general procedure H and 2-butylamino-4,6-di(pyrrolidineethoxy)aniline obtained was used directly for the next step.

Example 332 was formed employing phenylenediamine formed above (784 mg; 2 mmol) and 2-(3-diethylaminopropoxy)-4-[2-(4-chlorophenyl)ethoxy]benzaldehyde (858; 2.2 mmol) in ethanol (5 mL) following the general procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford 380 mg of Example 332.

MS m/z 760 (M+H)⁺

Example 333 (3-{1-Butyl-6-(3-diethylamino-propoxy)-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine

A solution of 2,4-difluorobenzaldehyde (2.13 g, 15.0 mmol) in DMF (10 ml) was added dropwise to a precooled (0° C.) solution of sodium 2-pyrrolidinoethoxide in DMF (50 ml), which was made by stirring a mixture of sodium hydride (600 mg, 15.0 mmol, 60% in mineral oil) and N-(2-hydroxyethyl)pyrrolidine (1.72 g, 15.0 mmol). The resulting reaction mixture was warmed to rt and stirred for additional 3 h. To the same reaction flask was introduced potassium carbonate (2.10 g, 15.0 mmol) and 3-fluoro-4-trifluoromethylphenol (2.7 g, 15.0 mmol) and the reaction mixture was heated at 90° C. as described in the General Procedure E for 2-alkoxy-4-aryloxybenzaldehydes. The crude product was purified by silica gel column chromatography using dichloromethane and 5% methanol in dichloromethane as eluent, to give 2-(2-pyrrolidineethoxy)-4-(3-fluoro-4-trifluoromethyl)phenoxybenzaldehyde (2 g) as a brown oil.

MS m/z 399 (M+FI)⁺

Example 333 was formed employing the aldehyde formed above (873 mg; 2.2 mmol) and 2-butylamino-4,6-di(3-diethylaminopropoxy)aniline (848; 2.0 mmol) following the general procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford 390 mg of Example 333.

MS m/z 800 (M+H)⁺

Example 334 {3-[1-Butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine

MsCl (1.4 mL, 18.0 mmol) was added dropwise at 0° C. to a stirred solution of pyrrolidineehanol (1.90 mL, 16.0 mmol), TEA (2.8 mL, 20.0 mmol) in anhydrous DCM (20 mL), and the mixture was stirred at rt for 1 h. After the removal of the solvent in vacuo, the solid residue was mixed with 3,5-difluoro-4-nitrophenol (1.75 g; 10 mmol) and K2CO3 (5.5 g; 40 mmol) following General Procedure F1. The product, 2,6-difluoro-4-(N-pyrrolidineethoxy)nitrobenzene (1.5 g) was used directly.

To a stirred solution of 2,6-difluoro-4-(N-pyrrolidineethoxy)nitrobenzene obtained above (1.4 g; 5.1 mmol) and triethylamine (1.4 mL; 10.0 mmol) in DMF (10 mL), a solution of n-butylamine (505 μL; 5.1 mmol) in DMF (3 mL) was added according to General Procedure G1. The crude product, 2-(n-butylamino)-4-(N-pyrrolidineethoxy)-6-fluoronitrobenzene. (1.5 g) was used for further transformation without any purification.

A solution of 3-diethylaminopropanol (652 μL; 4.4 mmol) in anhydrous THF 4.4 mL was added with powdered KOBu^(t) (493 mg; 4.4 mmol) and stirred at rt for 5 min. This solution was added dropwise to a stirred solution of 2-(n-butylamino)-4-(N-pyrrolidineethoxy)-6-fluoronitrobenzene (1.32 g; 4.0 mmol) in anhydrous THF (10 mL) according to General Procedure G2. The crude product, 2-(n-butylamino)-4-(N-pyrrolidineethoxy)-6-(N,N-diethylaminopropoxy)nitrobenzene (1.5 g) was used directly.

The nitro compound formed above (1.31 g, 4 mmol) dissolved in MeOH (20 mL) was hydrogenated following general procedure H. The product obtained (1.15 g) was used directly for the next step.

Example 334 was formed employing phenylenediamine formed above (816 mg; 2 mmol) and 2-(2-pyrrolidineethoxy)-4-(3-fluoro-4-trifluoromethyl)phenoxybenzaldehyde (873 mg; 2.2 mmol) in ethanol (5 mL) following general procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford 375 mg of Example 334.

MS m/z 784 (M+H)⁺

Example 335 {3-[2-[1-Butyl-6-(3-diethylamino-propoxy)-4-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]-5-(4-fluoro-3-trifluoromethyl-phenoxy)-phenoxy]-propyl}-diethyl-amine

A solution of 2,4-difluorobenzaldehyde (2.13 g, 15.0 mmol) in DMF (10 ml) was added dropwise to a precooled (0° C.) solution of sodium 3-diethylaminopropoxide in DMF (50 ml), which was made by stirring a mixture of sodium hydride (600 mg, 15.0 mmol, 60% in mineral oil) and 3-diethylaminopropanol (1.97 g, 15.0 mmol). The resulting reaction mixture was warmed to rt and stirred for additional 3 h. To the same reaction flask was introduced potassium carbonate (2.10 g, 15.0 mmol) and 3-fluoro-4-trifluoromethylphenol (2.7 g, 15.0 mmol) and the reaction mixture was heated at 90° C. as described general procedure E. The crude product was purified by silica gel column chromatography using dichloromethane and 5% methanol in dichloromethane as eluent, to give 2-(3-diethylaminopropoxy)-4-(3-fluoro-4-trifluoromethyl)phenoxybenzaldehyde (2.2 g).

Methanesulfonyl chloride (General Procedure P2) (1.55 mL, 20.0 mmol) was added dropwise at 0° C. to a stirred solution of 3-diethylaminopropanol (2.70 mL, 18.0 mmol), TEA (2.8 mL, 20.0 mmol) in anhydrous DCM (30 mL), and the mixture was stirred at rt for 1 h. After the removal of the solvent in vacuo, the solid residue was mixed with 3,5-difluoro-4-nitrophenol (2.65 g; 15 mmol) and K₂CO₃ (6.9 g; 50 mmol) according to General Procedure F1. The crude product, 2,6-difluoro-4-(3-diethylaminopropoxy)nitrobenzene (3.9 g) was used for further transformation.

To a stirred solution of 2,6-difluoro-4-(3-diethylaminopropoxy)nitrobenzene obtained above (1.9 g; 6.6 mmol) and triethylamine (1.4 mL; 10.0 mmol) in DMF (12 mL), a solution of n-butylamine (656 μL; 6.6 mmol) in DMF (4 mL) was added dropwise at it within 15 min, and the rest was followed as described in the general methods. The crude product, 2-(n-butylamino)-4-(3-diethylaminopropoxy)-6-fluoronitrobenzene (2.0 g) was used for further transformation without any purification.

A solution of 3-diethylaminopropanol (516 □L; 4.4 mmol) in anhydrous THF 4.4 mL was added with powdered KOBu^(t) (493 mg; 4.4 mmol) and stirred at room temperature for 5 min. This solution was added dropwise to a stirred solution of 2-(n-butylamino)-4-(3-diethylaminopropoxy)-6-fluoronitrobenzene (1.37 g; 4.0 mmol) in anhydrous THF (10 mL) at 0° C. under a N₂ stream. The reaction mixture was maintained at 0° C. for 1 h at which time the reaction was complete the rest was followed as described in the general methods. The crude product, 2-(n-butylamino)-4-(3-diethylaminopropoxy)-6-(N-pyrrolidineethoxy)nitrobenzene. (1.6 g) was used for further transformation without any purification.

The nitro compound formed above (1.31 g, 4 mmol) dissolved in MeOH (20 mL) was hydrogenated following the general procedure and 2-(n-butylamino)-4-(N-pyrrolidineethoxy)-6-(N,N-diethylaminopropoxy)aniline (1.15 g) obtained was used directly for the next step reaction without further purification.

Example 335 was formed employing phenylenedimaine formed above (816 mg; 2 mmol) and 2-(3-diethylaminopropoxy)-4-(3-fluoro-4-trifluoromethyl)phenoxybenzaldehyde (910 mg; 2.2 mmol) in ethanol (5 mL) following the general procedure. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford 380 mg of Example 335.

MS m/z 800 (M+H)⁺

Example 336 {3-[2-[1-Butyl-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]-5-(4-fluoro-3-trifluoromethyl-phenoxy)-phenoxy]-propyl}-diethyl-amine

A solution of 2,4-difluorobenzaldehyde (2.13 g, 15.0 mmol) in DMF (10 ml) was added dropwise to a precooled (0° C.) solution of sodium 3-dimethylaminopropoxide in DMF (50 ml), which was made by stirring a mixture of sodium hydride (600 mg, 15.0 mmol, 60% in mineral oil) and 3-dimethylaminopropanol (1.55 g, 15.0 mmol). The resulting reaction mixture was warmed to rt and stirred for additional 3 h. To the same reaction flask was introduced potassium carbonate (2.10 g, 15.0 mmol) and 3-fluoro-4-trifluoromethylphenol (2.7 g, 15.0 mmol) and the reaction mixture was heated at 90° C. as described in General Procedure E for 2-alkoxy-4-aryloxybenzaldehydes. The crude product was purified by silica gel column chromatography using dichloromethane and 5% methanol in dichloromethane as eluent, to give 2-(3-dimethylaminopropoxy)-4-(3-fluoro-4-trifluoromethyl)phenoxybenzaldehyde (2.0 g).

Example 336 was formed employing the aldehyde formed above (823 mg; 2.2 mmol) and 2-butylamino-4,6-di(pyrrolidineethoxy)aniline (784; 2.0 mmol) in ethanol (5 mL) following General Procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford 380 mg of Example 336.

MS m/z 784 (M+H)⁺

Example 337 {3-[3-butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-7-(2-pyrrolidin-1-yl-ethoxy)-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine

A solution of 2,4-difluorobenzaldehyde (2.13 g, 15.0 mmol) in DMF (10 ml) was added dropwise to a precooled (0° C.) solution of sodium 3-dimethylaminopropoxide in DMF (50 ml), which was made by stirring a mixture of sodium hydride (600 mg, 15.0 mmol, 60% in mineral oil) and 3-dimethylaminopropanol (1.55 g, 15.0 mmol). The resulting reaction mixture was warmed to rt and stirred for additional 3 h. To the same reaction flask was introduced potassium carbonate (2.10 g, 15.0 mmol) and 3-fluoro-4-trifluoromethylphenol (2.7 g, 15.0 mmol) and the reaction mixture was heated at 90° C. as described in General Procedure E for 2-alkoxy-4-aryloxybenzaldehydes. The crude product was purified by silica gel column chromatography using dichloromethane and 5% methanol in dichloromethane as eluent, to give 2-(3-dimethylaminopropoxy)-4-(3-fluoro-4-trifluoromethyl)phenoxybenzaldehyde (2.0 g).

Example 337 was formed employing the aldehyde formed above (823 mg; 2.2 mmol) and 2-butylamino-4,6-di(pyrrolidineethoxy)aniline (784; 2.0 mmol) in ethanol (5 mL) following General Procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford 380 mg of Example 337.

MS m/z 759 (M+H)⁺

Example 338 (3-{2-[1-Butyl-4-(3-diethylamino-propoxy)-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine

2-(3-diethylaminopropoxy)-4-[2-(4-chlorophenyl)ethoxy]benzaldehyde (858; 2.2 mmol) and 2-(n-butylamino)-4-(N-pyrrolidineethoxy)-6-(N,N-diethylaminopropoxy)aniline (816 mg; 2 mmol) were condensed to form the benzimidazole following General Procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford 390 mg of Example 338.

MS m/z 776 (M+H)⁺

The following Examples were synthesized according to the Methods employed for Examples 327-338;

Example Name 339 {3-[1-butyl-2-[4-(3,4-dichloro-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}- diethyl-amine 340 {3-[2-[2,4-bis-(3-diethylamino-propoxy)-phenyl]-1-butyl-6-(4-tert-butyl- phenoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 341 {3-[1-butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(pyridin-2-ylmethoxy)- phenyl]-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yl]-phenyl}- diethyl-amine 342 {3-[2-[4-[2-(4-Chloro-phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]- 6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl- amine 343 1-Butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 344 {3-[1-Butyl-2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl- ethoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]- propyl}-diethyl-amine 345 (3-{6-(3-Diethylamino-propoxy)-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)- 2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)- diethyl-amine 346 {3-[2-[1-Butyl-4-(3-diethylamino-propoxy)-6-(2-pyrrolidin-1-yl-ethoxy)-1H- benzoimidazol-2-yl]-5-(4-fluoro-3-trifluoromethyl-phenoxy)-phenoxy]- propyl}-diethyl-amine 347 {3-[3-Butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl- ethoxy)-phenyl]-7-(2-pyrrolidin-1-yl-ethoxy)-3H-benzoimidazol-5-yloxy]- propyl}-diethyl-amine 348 {3-[1-butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazol-4-yloxy]-propyl}- diethyl-amine 349 {3-[2-[1-butyl-4,6-bis-(2-pyrrolodin-1-yl-ethoxy)-1H-benzimidazol-2-yl]-5- (4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-propyl}-diethyl-amine 350 {3-[1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-3-diethylaminomethyl- phenyl}-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}- diethyl-amine 351 {3-[2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(pyridin-2-ylmethoxy)-phenyl]-6-(3- diethylamino-propoxy)-1H-benzimidazol-4-yl]-propyl}-diethyl-amine 352 3-(7-Butoxy-3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-2- cyclopentylmethoxy-phenyl}-3H-benzoimidazol-5-yloxy)-propan-1-ol 353 3-(7-Butoxy-2-{4-[2-(4-chloro-phenyl)-ethoxy]-2-cyclopentylmethoxy- phenyl}-3H-benzoimidazol-5-yloxy)-propan-1-ol 354 (3-{1-Butyl-6-(3-diethylamino-propoxy)-2-[4-(4-fluoro-3-trifluoromethyl- phenoxy)-2-(pyridin-2-ylmethoxy)-phenyl]-1H-benzoimidazol-4-yloxy}- propyl)-diethyl-amine 355 {3-[2-[1-Butyl-4,6-bis-(3-diethylamino-propoxy)-1H-benzoimidazol-2-yl]-5- (4-fluoro-3-trifluoromethyl-phenoxy)-phenoxy]-propyl}-diethyl-amine 356 2-(3,5-bis-benzyloxy-phenyl)-1-butyl-4,6-bis-(2-pyrrolodin-1-yl-ethoxy)- 1H-benzimidazole 357 {3-[2-[1-butyl-4,6-bis-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-5- (4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-propyl}-diethyl-amine 358 1-butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-pyrrol-1-yl-ethoxy)-phenyl]- 4,6-bis-(2-pyrrolodin-1-yl-ethoxy)-1H-benzoimidazole 359 {3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]-2-(3-diethylamino-propoxy)-phenyl}- 6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl- amine 360 {3-[1-Butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(pyridin-3-ylmethoxy)- phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 361 (3-{3-Butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(3-diethylamino-propoxy)- phenyl]-7-isopropoxy-3H-benzoimidazol-5-yloxy}-propyl)-diethyl-amine 362 {3-[1-Butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(pyridin-4-ylmethoxy)- phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 363 {3-[2-[4-[2-(4-Chloro-phenyl)-ethoxy]-2-(pyridin-4-ylmethoxy)-phenyl]-6- (3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl- amine 364 1-Butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(pyridin-2-ylmethoxy)- phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 365 2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,7- bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazole 366 {3-[1-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-2-methoxy-phenyl}-6-(3- diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 367 {3-[2-{4-[2-(4-Chloro-phenyl)-ethoxy]-2-methoxy-phenyl}-6-(3- diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 368 (3-{1-Butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(3-diethylamino-propoxy)- phenyl]-6-isopropoxy-1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine 369 {3-[1-Butyl-2-[4-(4-chloro-3-methyl-phenoxy)-2-(pyridin-2-ylmethoxy)- phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 370 1-Butyl-2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-2-cyclopentylmethoxy- phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 371 (2-{1-butyl-6-(2-dimethylamino-ethoxy)-2-[4-(4-fluoro-3-trifluoromethyl- phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzoimidazole-4- yloxy}-ethyl)-dimethyl-amine 372 2-[1-butyl-4,6-bis-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-5-[2-(4- chloro-phenyl)-ethoxy]-phenol 373 1-Butyl-2-[4-(4-chloro-3-methyl-phenoxy)-2-(pyridin-2-ylmethoxy)-phenyl]- 4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 374 2-[4-(4-Chloro-3-trifluoromethyl-phenoxy)-2-cyclopentylmethoxy-phenyl]- 4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 375 2-[4-(4-Fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 376 {3-[2-(3,5-bis-benzyloxy-phenyl)-1-butyl-6-(3-diethylamino-propoxy)-1H- benzimidazol-4-yloxy]-propyl}-diethyl-amine 377 (3-{1-butyl-6-(3-dimethylamino-propoxy)-2-[4-(3-fluoro-phenoxy)-2-(2- pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzoimidazole-4-yloxy}-propyl)- diethyl-amine 378 {3-[2-{1-butyl-4-(4-chloro-benzyloxy)-6-(2-pyrrolidin-1-yl-ethoxy)-1H- benzimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)- diethyl-amine 379 {3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]-2-(3-diethylamino-propoxy)-phenyl]- 6-(3-diethylamino-propoxy)-3H-benzimidazol-4-yloxy]-propyl}-diethyl- amine 380 {3-[2-[4-(3,4-dichloro-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6-(3- diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 381 {3-[1-Butyl-2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-2- cyclopentylmethoxy-phenyl]-6-(3-diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}-diethyl-amine 382 {3-[2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-2-cyclopentylmethoxy- phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine 383 (3-{1-butyl-6-(4-tert-butyl-phenoxy)-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(3- diethylamino-propoxy)-phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl- amine 384 2-{2,4-bis-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-1-butyl-4,6-bis-(2- pyrrolidin-1-yl-ethoxy)-1H-benzimidazole 385 (2-{1-butyl-6-(2-dimethylamino-ethoxy)-2-[4-(3-fluoro-phenoxy)-2-(2- pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzoimidazole-4-yloxy}-ethyl)- dimethyl-amine 386 {3-[2-[4-(3,5-bis-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]- propyl}-diethyl-amine 387 {3-[1-butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}- diethyl-amine 388 (3-{2-(1-Butyl-4,6-diisopropoxy-1H-benzoimidazol-2-yl)-5-[2-(4-chloro- phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine 389 {3-[1-butyl-2-{3-[2-(4-chloro-phenyl)-ethoxy]-4-diethylaminomethyl- phenyl}-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}- diethyl-amine 390 (3-{1-Butyl-6-(3-diethylamino-propoxy)-2-[4-fluoro-2-(2-pyrrolidin-1-yl- ethoxy)-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine 391 (2-{1-butyl-6-fluoro-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2- pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzoimidazol-4-ylsulfanyl}-ethyl)- dimethyl-amine 392 {3-[1-Butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-3-(3-diethylamino-propoxy)- phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}- diethyl-amine

Example 393 (4-benzyloxy-benzyl)-[1-butyl-6-(3-diethylaminopropoxy)-1-H-benzimidazol-2-ylmethyl]-hexyl-amine

To 2-butylamino-4-(3-diethylaminopropoxy)aniline (3.44 g; 11.7 mmol) and BOC-glycine (2.46 g, 14.1 mmol) in DCM (20 mL) was added DCC (2.90 g, 14.1 mmol) and the reaction mixture was stirred for 4 h. The solid was removed by filtration and the filtrate was concentrated to afford the desired product. The crude product was used for further transformation without any purification.

To the product (11.7 mmol) obtained above in dioxane (7.5 mL) was added acetic acid (2.5 mL) and the reaction mixture was heated at 80° C. until the reaction was complete. Saturated sodium bicarbonate was added and the mixture was extracted with EtOAc. The combined organic layer was washed with water and brine, dried over sodium sulfate. Evaporation of the solvent in vacuo afforded desired 1-butyl-2-boc-aminomethyl-6-(3-diethylaminopropxy)-1-H-benzimidazole. The product obtained was treated with 4 N HCl in dioxane according to General Procedure H to give 1-butyl-2-aminomethyl-6-(3-diethylaminopropxy)-1-H-benzimidazole hydrochloride.

To 1-butyl-2-aminomethyl-6-(3-diethylaminopropxy)-1-H-benzimidazole (1.0 mmol) in DCM (8 mL) were added Et₃N (3.0 mmol) and 4-benzoxybenzaldehyde (1.0 mmol) and the mixture was stirred for 4 h, then NaBH(OAc)₃ (4.0 mmol) was added and stirred for another 4 h, then sodium bicarbonate was added and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, and dried over sodium sulfate. The crude product was purified by silica gel column chromatography using DCM with a gradual increment of MeOH (1% to 10%) as eluent to afford 1-butyl-2-(4-benzyloxy-benzyl)-aminomethyl-6-(3-diethylaminopropoxy)-1-H-benzimidazole.

To 1-butyl-2-(4-benzyloxy-benzyl)-aminomethyl-6-(3-diethylaminopropxy)-1-H-benzimidazole (16 mg, 0.03 mmol) in DCM (2 mL) were added hexanal (8.3 mg, 0.083 mmol) and the mixture was stirred for 10 min, then NaBH(OAc)₃ (32 mg, 0.15 mmol) was added and stirred for 3 h, then sodium bicarbonate was added and the mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with brine, and dried over sodium sulfate. The crude product was purified by silica gel column chromatography using DCM with a gradual increment of MeOH (1% to 5%) as eluent to afford 14 mg of Example 393.

MS m/z 613 [M+H]⁺

Example 394 (4-benzyloxy-benzyl)-[1-butyl-6-(3-diethylaminopropoxy)-1-H-benzimidazol-2-ylmethyl]-isobutyl-amine

To 1-butyl-2-(4-benzyloxy-benzyl)-aminomethyl-6-(3-diethylaminopropxy)-1-H-benzimidazole (16 mg, 0.03 mmol) in DCM (2 mL) were added isbutrylaldehyde (8.6 mg, 0.10 mmol) and the mixture was stirred for 10 min, then NaBH(OAc)₃ (32 mg, 0.15 mmol) was added and stirred for 3 h, then sodium bicarbonate was added and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, and dried over sodium sulfate. The crude product was purified by silica gel column chromatography using DCM with a gradual increment of MeOH (1% to 5%) as eluent to afford 12 mg of Example 394.

MS m/z 585 [M+H]⁺

Example 395 [3-(2-[(4-benzyloxy-benzyl)-cyclopentylmethyl-amino]-methyl}-3-butyl-3-H-benzimidazol-5-yloxy)-propyl]-diethylamine

To 1-butyl-2-(4-benzyloxy-benzyl)-aminomethyl-6-(3-diethylaminopropxy)-1-H-benzimidazole (16 mg, 0.03 mmol) in DCM (2 mL) were added cyclopentyl carboxaldehyde (11 mg, 0.10 mmol) and the mixture was stirred for 10 min, then NaBH(OAc)3 (32 mg, 0.15 mmol) was added and stirred for 3 h, then sodium bicarbonate was added and the mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with brine, and dried over sodium sulfate. The crude product was purified by silica gel column chromatography using DCM with a gradual increment of MeOH (1% to 5%) as eluent to afford 8.0 mg of Example 395.

MS m/z 611 [M+H]⁺

Example 396 N-(4-benzyloxy-benzyl)-N-[1-butyl-6-(3-diethylaminopropoxy)-1-H-benzimidazol-2-ylmethyl]-benzamide

To 1-butyl-2-(4-benzyloxy-benzyl)-aminomethyl-6-(3-diethylaminopropxy)-1-H-benzimidazole (32 mg, 0.06 mmol) in DCM (3 mL) were added benzoyl chloride (34 mg, 0.24 mmol), TEA (24 mg, 0.24 mmol), DMAP (catalytic amount) and the mixture was stirred for 12 h, then sodium bicarbonate was added and the mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with brine, and dried over sodium sulfate. The crude product was purified by silica gel column chromatography using DCM with a gradual increment of MeOH (0 to 1%) as eluent to afford 30 mg of Example 396.

MS m/z 633 [M+H]⁺

Example 397 (3-{3-butyl-2-[(dibenzylamino)-methyl]-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine

To 1-butyl-2-aminomethyl-6-(3-diethylaminopropxy)-1-H-benzimidazole (15 mg, 0.034 mmol) in DCM (2 mL) were added Et₃N (0.10 mmol) and benzaldehyde (180 mg, 0.17 mmol) and the mixture was stirred for 10 min, then NaBH(OAc)₃ (72 mg, 0.34 mmol) was added and stirred for 3 h, then sodium bicarbonate was added and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, and dried over sodium sulfate. The crude product was purified by silica gel column chromatography using DCM with a gradual increment of MeOH (1% to 2%) as eluent to afford 10 mg of Example 397.

MS m/z 513 [M+H]⁺

The following Examples were synthesized according to the Methods employed for Examples 393-397;

Example Name 398 (3-{2-[(4-benzyloxy-benzylamino)-methyl]-3-butyl-3H-benzimidazol-5- yloxy}-propyl)-diethyl-amine 399 N-(4-benzyloxy-benzyl)-N-[1-butyl-6-(3-diethylamino-propoxy)-1H- benzimidazol-2-ylmethyl]-methanesulfonamide 400 N-(4-benzyloxy-benzyl)-N-[1-butyl-6-(3-diethylamino-propoxy)-1H- benzimidazol-2-ylmethyl]-acetamide 401 {3-[3-butyl-2-({4-[2-(4-chloro-phenyl)-ethoxy]-benzylamino}-methyl)-3H- benzimidazol-5-yloxy)-propyl]-diethyl-amine 402 [3-(2-{[Bis-(4-benzyloxy-benzyl)-amino]-methyl}-3-butyl-3H- benzoimidazol-5-yloxy)-propyl]-diethyl-amine 403 [3-(2-{[Benzyl-(4-benzyloxy-benzyl)-amino]-methyl}-3-butyl-3H- benzoimidazol-5-yloxy)-propyl]-diethyl-amine

Example 404 {3-[4-(2-butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide (2.2 mmol) in THF was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then treated with cold H₂O and extracted with EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10 mg), according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-alkoxyaniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion, according to General Procedure Q1. After cooling to rt, the reaction mixture was quenched using cold water (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone.

To a stirred solution of the 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the residue was treated with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by chromatography (Silica gel).

To a stirred solution of the N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (1.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at it until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of 1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 4.8 mmol) was added, followed by slow addition of valeryl chloride (2 eq., 3.2 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in DCM. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in acetic acid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography on silica gel (yield: 270 mg).

MS m/z 561 (M+H)⁺:

¹H NMR: δ 7.85 (s, 1H), 7.71 (d, 2H), 7.56 (d, 2H), 7.32 (m, 4H), 7.24 (d, 2H), 7.06 (d, 2H), 4.25 (t, 2H), 3.43 (t, 2H), 3.35 (m, 6H), 3.12 (t, 2H), 2.97 (t, 2H), 2.31 (m, 2H), 1.65 (m, 2H), 1.41 (t, 6H), 1.37 (m, 2H), 0.85 (t, 3H) ppm.

Example 405 {3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-isobutyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide (2.2 mmol) in THF was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. until completion, as indicated by TLC or HPLC. The reaction mixture was then treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crude product was used directly for further transformation without any purification, or after purifying using silica gel column chromatography.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-alkoxyaniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (1.2 mmol) in DMF (10 mL) at rt, solid potassium carbonate (3.0 mmol) was added. 4-chlorophenethyl mesylate (1.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched by removing solvent in vacuuo and treating the residue with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (20 ml) and washed with H₂O (2×10 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated acetophenone was used for further transformation without any purification or after purifying using silica gel column chromatography.

To a stirred solution of the 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a stirred solution of the N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq, 2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq 6 mmol) was added, followed by a slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (1.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained from 2-4% MeOH/DCM.

To a stirred solution of 1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanone described above (2 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq, 6 mmol) was added, followed by a slow addition of isovaleryl chloride (3 eq, 6 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (2 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM (Yield: 390 mg).

MS m/z 560 (M+H)⁺

¹H NMR: δ 7.86 (s, 1H), 7.65 (d, 2H), 7.59 (d, 2H), 7.31 (m, 4H), 7.23 (d, 2H), 7.13 (d, 2H), 4.51 (m, 2H), 3.42 (t, 2H), 3.31 (m, 6H), 3.05 (t, 2H), 2.87 (t, 2H), 2.31 (m, 2H), 1.95 (m, 1H), 1.49 (t, 6H), 0.86 (d, 6H) ppm.

Example 406 [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM (25 mL), TEA (40 mmol, 2 eq) was added and the mixture was cooled to 0° C. To this mixture, methanesulfonyl chloride (30 mmol, 1.5 eq) was added slowly with stirring and the reaction mixture stirred at 0° C. for an hour and at rt for another hour (until the reaction was complete by HPLC). The solvent was removed and saturated aqueous sodium bicarbonate was added. The product was extracted with EtOAc (3×) and washed with sodium bicarbonate and water. The solvent was removed in vacuuo.

The mesylate from the previous step (20 mmol, 1 eq) was dissolved in anhydrous DMF (25 mL), and 4-hydroxyacetophenone (20 mmol, 1 eq) and potassium carbonate (60 mmol, 3 eq) were added. The mixture was heated under reflux at 85° C. for 18 h (until the reaction was complete by HPLC), after which it was cooled to rt. Saturated aqueous sodium bicarbonate was added to the mixture, which was then transferred to a separatory funnel. The product 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was extracted with EtOAc and washed with sodium bicarbonate and water. The solvent was removed in vacuuo and the product was purified by flash chromatography (going by increasing gradient up to 10% MeOH in DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (5 mmol) in anhydrous MeOH (10 mL) at 0° C., pyrrolidone hydrotribromide (6 mmol, 1.2 eq) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a solution of 4-chlorophenoxy aniline (1 eq, 5 mmol) in anhydrous DMF (10 mL), DIEA (3 eq 15 mmol) was added, followed by addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (5 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product obtained from 2-4% MeOH/DCM.

To a stirred solution of 2-[4-(4-chlorophenoxy)-phenylamino]-1-[4-(3-diethylamino-propoxy)-phenyl]-ethanone (2 mmol) in anhydrous DCM (8 mL) at 0° C., TEA (3 eq, 6 mmol) was added, followed by a slow addition of valeryl chloride (3 eq, 6 mmol). The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion as indicated by TLC or HPLC, according to General Procedure R3. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (2 mmol) in acetic acid (8 mL), ammonium acetate (20 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography on silica gel elutiopn with 4-6% MeOH/DCM) (yield 424 mg).

MS m/z 532 (M+H)⁺:

¹H NMR (CDCl₃): δ 7.68 (d, 2H), 7.34 (d, 2H), 7.28 (d, 2H), 7.14 (s, 1H), 7.07 (d, 2H), 7.01 (d, 2H,), 6.89 (d, 2H) 4.04 (t, 2H), 2.64-2.78 (m, 8H), 1.99 (m, 2H), 1.64 (m, 2H), 1.30 (m, 2H), 1.09 (t, 6H), 0.83 (t, 3H) ppm.

Example 407 1-[4-(4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-butyl]-piperazine

To a stirred solution of 4-benzyloxyacetophenone (7.0 mmol) in anhydrous DCM (30.0 mL) and MeOH (5.0 mL) at rt, pyridinium bromide perbromide (1.1 eq.) was added. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC. The mixture was diluted with EtOAc (100 ml) and washed with H₂O (2×50 ml), brine (30 ml) and dried with magnesium sulfate. The solvent was then removed in vacuuo to give a white solid. The alpha-bromoacetophenone was used for further transformation without further purification.

To a stirred solution of 4-(4-fluoro-3-trifluoromethyl-phenoxy)-aniline (1.64 mmol) in anhydrous DMF (30 mL) DIEA (3 eq) was added, followed by slow addition of the alpha-bromoacetophenone described above (2 eq), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC and HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in Et₂O. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography on silica gel (elution with 5-20% EtOAc/Hexane).

To a stirred solution of alkylated aniline described above (1.0 mmol) in anhydrous THF (20 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed by slow addition of valeryl chloride (3 eq, 3.0 mmol). The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to ambient temperature until completion as indicated by TLC and HPLC, according to General Procedure R3. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.0 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography on silica gel (elution with 5-15% EtOAc/Hexane). MS: m/z 562 (M+H)⁺)

The benzyl imidazole from above was dissolved in MeOH (20 mL), and Pd/C (100 mg) was added and the heterogeneous mixture was stirred overnight under hydrogen atmosphere using a balloon, according to General Procedure H. The catalyst was removed by filtration. The solvent was removed in vacuuo, and the crude phenol (MS: m/z 472 (M+H)⁺) was used directly.

To a stirred solution of the phenol (0.16 mmol) obtained above in anhydrous DMF (5 mL) solid sodium hydride (60% dispersion in oil; 1.0 mmol) was added in portions. After the addition, a solution of 4-bromobutyl methanesulfonate (0.2 mmol) (prepared as described earlier) in anhydrous THF (2 mL) was added to the reaction mixture. The reaction was then allowed to proceed at rt. Upon completion of the reaction, piperazine (5.0 eq) was added. The mixture was stirred overnight. Et₂O (30 mL) was added to the reaction mixture followed by H₂O (10 mL). The organic layer was washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. The solvent was removed in vacuuo. Product was purified by column chromatography on silica gel (elution with 5-10% MeOH/DCM) (yield 54.0 mg)

MS m/z 612 (M+H)⁺:

Example 408 4-(4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-1-methyl-piperidine

To a stirred solution of 4-benzyloxyacetophenone (7.0 mmol) in anhydrous DCM (30.0 mL) and MeOH (5.0 mL) at rt, pyridinium bromide perbromide (1.1 eq.) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC. The mixture was diluted with EtOAc (100 ml) and washed with H₂O (2×50 ml), brine (30 ml) and dried with magnesium sulfate. The solvent was then removed in vacuuo to give a white solid. The alpha-bromoacetophenone was used for further transformation without further purification.

To a stirred solution of 4-(4-fluoro-3-trifluoromethyl-phenoxy)-aniline (1.64 mmol) in anhydrous DMF (30 mL) DIEA (3 eq) was added, followed by slow addition of the alpha-bromoacetophenone described above (2 eq), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC and HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in Et₂O. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography on silica gel (elution with 5-20% EtOAc/Hexane).

To a stirred solution of alkylated aniline described above (1.0 mmol) in anhydrous THF (20 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed by slow addition of valeryl chloride (3 eq, 3.0 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to it until completion. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.0 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography on silica gel (elution with 5-15% EtOAc/Hexane).

MS: m/z 562 (M+H)⁺)

The above product was dissolved in MeOH (20 mL), and Pd/C (100 mg) was added and the heterogeneous mixture was stirred overnight under hydrogen atmosphere using a balloon, according to General Procedure T2. The Pd/C was removed by filtration. The solvent was removed in vacuuo, and the crude 4-(1-{4-[4-fluoro-3-(trifluoromethyl)phenoxy]phenyl}-2-butyl-1H-imidazol-4-yl)phenol (MS: m/z 472 (M+H)⁺) was used directly.

A stirred solution of the 4-(1-{4-[4-fluoro-3-(trifluoromethyl)phenoxy]phenyl}-2-butyl-1H-imidazol-4-yl)phenol (1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid sodium hydride (60% dispersion in oil; 1.0 mmol), added in portions. The mesylate of 1-methylpiperidin-4-ol (1.5-2.0 eq) was then added to the reaction mixture, which was heated at 90° C. overnight, according to General Procedure T3. After cooling the mix to rt, Et₂O (30 mL) was added to the reaction mixture followed by H₂O (10 mL). The organic layer was washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. The solvent was removed in vacuuo. Pure imidazole was obtained from chromatography in 5-10% MeOH/DCM (yield 14 mg).

MS m/z value (M+H)⁺: 569

¹H NMR (CDCl₃): δ7.70 (d, 2H), 7.20-7.35 (m, 5H), 7.14 (s, 1H), 7.08 (d, 2H), 6.92 (d, 2H), 4.4 (bs, 1H), 1.0 3.05 (m, 17H) ppm.

Example 409 1-[5-(4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-pentyl]-piperazine

To a stirred solution of 4-benzyloxyacetophenone (7.0 mmol) in anhydrous DCM (30.0 mL) and MeOH (5.0 mL) at rt, pyridinium bromide perbromide (1.1 eq.) was added. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC. The mixture was diluted with EtOAc (100 ml) and washed with H₂O (2×50 ml), brine (30 ml) and dried with magnesium sulfate. The solvent was then removed in vacuuo to give a white solid. The alpha-bromoacetophenone was used for further transformation without further purification.

To a stirred solution of 4-(4-fluoro-3-trifluoromethyl-phenoxy)-aniline (1.64 mmol) in anhydrous DMF (30 mL) DIEA (3 eq) was added, followed by slow addition of the alpha-bromoacetophenone described above (2 eq), according to General Procedure R2. The reaction mixture was stirred under nitrogen at it until completion, as indicated by TLC and HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in Et₂O. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained from 5-20% EtOAc/Hexane.

To a stirred solution of alkylated aniline described above (1.0 mmol) in anhydrous THF (20 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed by slow addition of valeryl chloride (3 eq, 3.0 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to ambient temperature until completion, as indicated by TLC and HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.0 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 5-15% EtOAc/Hexane.

MS: m/z 562 (M+H)⁺)

The above product was dissolved in MeOH (20 mL), and Pd/C (100 mg) was added and the heterogeneous mixture was stirred overnight under hydrogen atmosphere using a balloon, according to General Procedure H. The Pd/C was removed by filtration. The solvent was removed in vacuuo, and the crude phenol (MS: m/z 472 (M+H)⁺) was used for further transformation.

To a stirred solution of the imidazole (0.16 mmol) obtained above in anhydrous DMF (5 mL) solid sodium hydride (60% dispersion in oil; 1.0 mmol) was added in portions. After the addition, a solution of 5-bromopentyl methanesulfonate (0.2 mmol) anhydrous THF (2 mL) was added to the reaction mixture. The reaction was then allowed to proceed at rt. Upon completion of the reaction, piperazine (100 mg) added. The mixture was stirred overnight. Et₂O (30 mL) was added to the reaction mixture followed by H₂O (10 mL). The organic layer was washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. The solvent was removed in vacuuo. Pure product was obtained after chromatography on silica gel (elution with 5-10% MeOH/DCM) (yield 36.0 mg).

MS m/z 626 (M+H)⁺:

Example 410 {3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide (2.2 mmol) in THF was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. until completion, as indicated by TLC or HPLC. The reaction mixture was then treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crude product was used directly for further transformation without any purification, or after purifying using silica gel column chromatography.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (1.2 mmol) in DMF (10 mL) at rt, solid potassium carbonate (3.0 mmol) was added. 4-chlorophenethyl mesylate (1.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched by removing solvent in vacuuo and treating the residue with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (20 ml) and washed with H₂O (2×10 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated acetophenone was used for further transformation.

To a stirred solution of the 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidinone hydrotribromide (1.2 eq) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a stirred solution of the N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq, 2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq 6 mmol) was added, followed by a slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (1.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at it until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained from 2-4% MeOH/DCM .

The 1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanone obtained as above (1 mmol) was dissolved in formic acid (2 mL) and treated with ammonium formate (20 mmol). The resulting mixture was heated to 90° C. overnight. The reaction mixture was then cooled to it and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography on silica gel (elution with 4-6% MeOH/DCM) (yield 161 mg).

MS m/z 504 (M+H)⁺:

¹H NMR (CDCl₃): δ 7.77 (s, 1H), 7.73 (d, 2H), 7.38 (s, 1H), 7.10-7.35 (m, 6H), 6.97 (d, 2H), 6.92 (d, 2H), 4.17 (t, 2H), 4.06 (broad t, 2H), 3.07 (t, 2H), 2.81 (broad q, 4H) 1.95-2.15 (broad m, 4H), 1.17 (t, 6H) ppm.

Example 411 {3-[3-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 3-nitrophenol (2 mmol) in DMF (6 mL) at rt, solid potassium carbonate (4 mmol) was added. A solution of the mesylate of N,N-diethylaminopropanol (2.2 mmol) in DMF (2 mL) was then added to the reaction mixture and heated to 80° C. until completion, according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was then treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired N,N-diethyl-N-[3-(3-nitrophenoxy)propyl]amine. The crude product was used directly for further transformation.

The N,N-diethyl-N-[3-(3-nitrophenoxy)propyl]amine (1 mmol) was dissolved in MeOH (5 mL) and hydrogenated in the presence of 10% Pd/C (50 mg) until completion as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired N-[3-(3-aminophenoxy)propyl]-N,N-diethylamine, which was used directly for further transformation without further purification.

To a stirred solution of N-[3-(3-aminophenoxy)propyl]-N,N-diethylamine (1 mmol) in anhydrous DMF (3 mL), DIEA (3 mmol) was added followed by a slow addition of 1-bromo-4′-(4-chlorophenethoxy)acetophenone (0.8 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography on silica gel (elutiion with 2-4% MeOH/DCM).

The 1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanone obtained as above (0.5 mmol) was dissolved in formic acid (1 mL) and treated with ammonium formate (10 mmol). The resulting mixture was heated to 90° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography on silica gel (elution with 4-6% MeOH/DCM).

MS m/z value (M+H)⁺: 504

¹H NMR (CDCl₃): δ7.89 (s, 1H), 7.74 (d, 2H), 7.47 (s, 1H), 7.30-7.10 (m, 7H), 6.92 (d, 2H) 6.85 (t, 1H) 4.10-4.20 (m, 4H), 3.00-3.20 (m, 6H), 2.31 (broad, 2H), 1.36 (t, 6H) ppm.

Example 412 [3-(4-{1-[4-(4-tert-butyl-phenoxy)-phenyl]-1H-imidazol-4-yl)-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of potassium 4-tert-butyl-phenoxide (2.2 mmol) in THF (may be generated by adding the corresponding alcohol to a 1M solution of KOBu^(t) in THF) was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuo and the reaction mixture was treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crude product was used directly for further transformation.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion, as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered. The solvent was removed in vacuuo to afford the desired 4-alkoxyaniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (10 mL) at rt, solid K₂CO₃ (8.0 mmol) was added. The mesylate of N,N-diethylaminopropanol (prepared from the corresponding alcohol and methanesulfonyl chloride, 2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was diluted with H₂O and the product was isolated in EtOAc. The combined organic layers were washed with saturated sodium bicarbonate (2×15 ml), water (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified using silica gel column chromatography (elution with 2-3% MeOH/DCM).

To a stirred solution of the 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (1 mmol) described above 48% HBr (3 eq, 3 mmol) in DMSO (4 mL) was added. The reaction mixture was heated to 80° C. until completion, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was neutralized with 2N sodium hydroxide solution and the product was isolated in EtOAc. The combined organic layers were washed with H₂O (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude ketoaldehyde was used for further transformation.

To a stirred solution of the ketoaldehyde (1 mmol) in AcOH (5 mL) 4-tert-butyl-phenoxy aniline (1.2 eq., 1.2 mmol), formaldehyde (excess, ˜30 eq.) and ammonium acetate (excess, ˜30 eq.) were added, according to General Procedure R4. The reaction mixture was heated to 80° C. until completion, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was neutralized with saturated sodium bicarbonate solution and the product was isolated in EtOAc. Usual extractive work up gave the desired product, which was purified by column chromatography on silica gel (elution with 3-4% MeOH/DCM) (Yield 150 mg).

MS: m/z 498 (M+H)⁺

¹H NMR (CDCl₃): δ7.64 (s, 1H), 7.39 (d, 2H), 7.12 (s, 1H), 7.06 (d, 2H) 7.02 (d, 2H) 6.97 (m, 2H) 6.79 (d, 2H), 3.98 (t, 2H), 2.66 (m, 6H), 2.02 (m, 2H), 1.31 (s, 9H), 1.08 (t, 6H) ppm.

Example 413 [3-(4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of a potassium 4-fluoro-3-trifluoromethyl-phenoxide (2.2 mmol) in THF (may be generated by adding the corresponding alcohol to a 1M solution of potassium t-butoxide in THF) was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the reaction mixture was treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude product could be used directly for further transformation.

The 1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion, as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered. The solvent was removed in vacuuo to afford the desired 4-alkoxyaniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (10 mL) at rt, solid potassium carbonate (8.0 mmol) was added. The mesylate of N,N-diethylaminopropanol (prepared from the corresponding alcohol and methanesulfonyl chloride) (2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was diluted with water and the product was isolated in EtOAc. The combined organic layers were washed with saturated sodium bicarbonate (2×15 ml), water (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified using silica gel column chromatography. Pure product was obtained after elution with 2-3% MeOH/DCM. (yield 50-60%)

To a stirred solution of the 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (1 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq, 1.2 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the residue was treated with saturated sodium bicarbonate and the product was isolated in EtOAc. The combined organic layers were washed with water (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a stirred solution of the 4-fluoro-3-trifluoromethyl-phenoxy aniline (1.2 eq., 1.2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 3 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (1.0 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of alkylated aniline described above (1.0 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 3 mmol) was added, followed by slow addition of valeryl chloride (2 eq., 2.0 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with water and the product was isolated in DCM. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to it and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained after elution with 4-6% MeOH/DCM (Yield 175 mg).

MS m/z 584 (M+H)⁺

Example 414 diethyl-[3-(4-{1-[4-(4-trifluoromethoxy-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of potassium 4-trifluoromethoxy-phenoxide (2.2 mmol) in THF (may be generated by adding the corresponding alcohol to a 1M solution of KOBu^(t) in THF) was added dropwise under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuo and the reaction mixture was treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuo afforded the desired 4-alkoxynitrobenzene. The crude product was used directly for further transformation.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion, as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-alkoxyaniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (10 mL) at rt, solid K₂CO₃ (8.0 mmol) was added. The mesylate of N,N-diethylaminopropanol (prepared from the corresponding alcohol and methanesulfonyl chloride, 2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was diluted with H₂O and the product was isolated in EtOAc. The combined organic layers were washed with saturated sodium bicarbonate (2×15 ml), H₂O (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified using silica gel column chromatography. Pure product was obtained with 2-3% MeOH/DCM.

To a stirred solution of the 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (1 mmol) described above 48% HBr (3 eq, 3 mmol) in DMSO (4 mL) was added. The reaction mixture was heated to 80° C. until completion, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was neutralized with saturated sodium bicarbonate solution and the product was isolated in EtOAc. The combined organic layers were washed with water (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude ketoaldehyde was used for further transformation.

To a stirred solution of the ketoaldehyde (1 mmol) in AcOH (5 mL), 4-trifluoromethoxy-phenoxy-aniline (1.2 eq., 1.2 mmol), formaldehyde (excess, ˜30 eq.) and ammonium acetate (excess, ˜30 eq.) were added, according to General Procedure R4. The reaction mixture was heated to 80° C. until completion, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was neutralized with saturated sodium bicarbonate solution and the product was isolated in EtOAc. Usual extractive work up with EtOAc gave the desired product, which was purified by column chromatography on silica gel, elution with 3-4% MeOH/DCM) (Yield 130 mg).

MS: m/z 526 (M+H)⁺

¹H NMR (CDCl₃): δ7.91 (s, 1H), 7.41 (d, 2H), 7.28 (d, 2H), 7.05 (d, 2H), 6.98 (m, 4H) 6.81 (d, 2H) 3.99 (t, 2H), 2.96 (m, 6H), 2.18 (m, 2H), 1.22 (t, 6H) ppm.

Example 415 [3-(4-{2-butyl-1-[4-(3,4-dichloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM (25 mL), TEA (40 mmol, 2 eq) was added and the mixture was cooled to 0° C. To this mixture, methanesulfonyl chloride (30 mmol, 1.5 eq) was added slowly with stirring and the reaction mixture was stirred at 0° C. for an hour and at rt for another hour (until the reaction was complete by HPLC). The solvent was removed and saturated aqueous sodium bicarbonate was added. The product was extracted with EtOAc (3×) and washed with sodium bicarbonate and water. The solvent was removed in vacuuo.

The product from the previous step (20 mmol, 1 eq) was dissolved in anhydrous DMF (25 mL) to which 4-hydroxyacetophenone (20 mmol, 1 eq) and potassium carbonate (60 mmol, 3 eq) were added. The mixture was heated under reflux at 85° C. for 18 h (until the reaction was complete by HPLC), after which it was cooled to rt. Saturated aqueous sodium bicarbonate was added to the mixture, which was then transferred to a separatory funnel. The product was extracted with EtOAc and washed with sodium bicarbonate and water. The solvent was removed in vacuuo and the 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by flash chromatography (going by increasing gradient up to 10% MeOH in DCM).

3,4-Dichlorophenol (10 mmol) was dissolved in 15 ml of anhydrous DMF and potassium carbonate (30 mmol) was added with stirring at rt. 4-Fluoronitrobenzene (10 mmol) was added to this mixture, which was then heated under reflux at 80° C. for 18 h. The reaction was quenched with 30 ml of water and 30 ml of sodium bicarbonate, extracted with EtOAc (3×50 ml) and washed with sodium bicarbonate and water. The EtOAc layer was dried over anhydrous sodium sulfate and filtered, after which the solvent was removed in vacuuo.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOH (30 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-(3,4-dichlorophenoxy)aniline, which was used directly for further transformation without further purification.

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (6 mL) at 0° C., pyrrolidone hydrotribromide (2.4 mmol, 1.2 eq) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a solution of 4-(3,4-dichlorophenoxy) aniline (1 eq, 2 mmol) in anhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was added, followed by addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (2 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product obtained from 2-4% MeOH/DCM.

To a stirred solution of alkylated aniline described above (1 mmol) in anhydrous DCM (4 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed by a slow addition of valeryl chloride (3 eq, 3 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1 mmol) in acetic acid (4 mL), ammonium acetate (excess, ˜20 eq) was added according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography on silica gel (elution with 4-6% MeOH/DCM) (yield 170 mg).

MS m/z 567 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ 7.7 (d, 2H), 7.3 (m, 3H), 6.9-7.1 (m, 7H), 4.0 (t, 2H), 2.7 (m, 8H), 2.0 (m, 2H), 1.6 (m, 2H), 1.3 (m, 2H), 1.1 (t, 6H), 0.8 (t, 3H) ppm.

Example 416 [3-(4-{2-cyclobutyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (20 mmol), 4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt, solid potassium carbonate (60 mmol) was added and the reaction mixture was heated to 90° C. for 5 h (monitored by TLC), according to General Procedure L1. After cooling to rt, the reaction mixture was poured into cold H₂O (60 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with H₂O (2×40 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo to afford the desired 1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude product was used directly for further transformation without further purification.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (50 mg) until completion as indicated by TLC or LC-MS, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline, which was used directly for further transformation without purification (overall yield: 95%).

To a stirred solution of ice-cold 3-diethylaminopropanol (63 mmol) and TEA (80 mmol) dissolved in anhydrous DCM (50 mL), methanesulfonyl chloride (60 mmol) was added dropwise and the reaction mixture was stirred for 2 h at 0° C., followed by additional 1 h at rt. After the removal of the solvents in vacuuo, the crude mesylate was dissolved in DMF (100 mL). 4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol) were added, and the mixture was heated with stirring at 90° C. for 18 h (monitored by LC-MS). After cooling to rt, the reaction was quenched with cold H₂O (100 mL), and the resulting mixture was extracted with EtOAc (4×100 mL). The combined EtOAc extracts were washed with brine (3×60 ml), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield: 75%).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4 mmol) in MeOH (10 mL) at rt, pyrrolidone hydrotribromide (4.8 mmol) was added, according to General Procedure R1. The reaction mixture was stirred at rt for 1 h (monitored by LC-MS). The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was directly used for further transformation.

To a stirred solution of 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline (4.8 mmol) dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added followed by a slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained above (˜4 mmol), according to General Procedure R2. The reaction mixture was stirred at rt and under nitrogen until completion (˜5 h), as indicated by LC-MS. The reaction was quenched with saturated sodium bicarbonate (50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with brine (3×40 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude product was purified by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield: 64%).

To a stirred solution of the alkylated aniline described above (0.2 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (1.2 mmol, 6 eq) was added followed by a slow addition of cyclobutanecarbonyl chloride (0.6 mmol, 3 eq), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by LC-MS. The solvent was removed in vacuuo, and the crude amide was used directly for further transformation.

To a stirred solution of the amide described above (˜0.2 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜30 eq) was added according to General Procedure R4. The reaction mixture was stirred at 100° C. for 2-5 h (as monitored by LC-MS). The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate. The resulting mixture was extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with brine (3×20 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the pure product was obtained by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield 64 mg).

MS m/z 582 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ1.05 (t, 6H), 1.90-2.20 (m, 6H), 2.56 (m, 2H), 2.58 (q, 4H), 2.66 (t, 2H), 3.44 (m, 1H), 4.02 (t, 2H), 6.91 (d, 2H), 7.05 (d, 2H), 7.14 (s, 1H), 7.22-7.26 (m, 3H), 7.31 (d, 2H), 7.72 (d, 2H) ppm.

Example 417 [3-(4-{2-cyclopentyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (20 mmol), 4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt, solid potassium carbonate (60 mmol) was added, and the reaction mixture was heated to 90° C. for 5 h (monitored by TLC), according to General Procedure L1. After cooling to rt, the reaction mixture was poured into cold H₂O (60 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with H₂O (2×40 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo to afford the desired 1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude product was used directly for further transformation without further purification.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (50 mg) until completion as indicated by TLC or LC-MS, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline, which was used directly for further transformation without purification (overall yield: 95%).

To a stirred solution of ice-cold 3-diethylaminopropanol (63 mmol) and TEA (80 mmol) dissolved in anhydrous DCM (50 mL) was added dropwise methanesulfonyl chloride (60 mmol), and the reaction mixture was stirred for 2 h at 0° C. and followed by additional 1 h at rt. After the removal of the solvents in vacuuo, the crude mesylate was dissolved in DMF (100 mL). 4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol) were added, and the mixture was heated with stirring at 90° C. for 18 h (monitored by LC-MS). After cooling to rt, the reaction was quenched with cold H₂O (100 mL), and the resulting mixture was extracted with EtOAc (4×100 mL). The combined EtOAc extracts were washed with brine (3×60 ml), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield: 75%).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4 mmol) in MeOH (10 mL) at rt, pyrrolidone hydrotribromide (4.8 mmol) was added, according to General Procedure R1. The reaction mixture was stirred at rt for 1 h (monitored by LC-MS). The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was directly used for further transformation.

To a stirred solution of 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline (4.8 mmol) dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added, followed by a slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained above (˜4 mmol), according to General Procedure R2. The reaction mixture was stirred at rt and under nitrogen until completion (˜5 h), as indicated by LC-MS. The reaction was quenched with saturated sodium bicarbonate (50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with brine (3×40 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude product was purified by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield: 64%).

To a stirred solution of the alkylated aniline described above (0.2 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (1.2 mmol, 6 eq) was added, followed by a slow addition of cyclopentanecarbonyl chloride (0.6 mmol, 3 eq), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by LC-MS. The solvent was removed in vacuuo, and the crude amide was used directly for further transformation.

To a stirred solution of the amide described above (˜0.2 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜30 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 100° C. for 2-5 h (as monitored by LC-MS). The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate. The resulting mixture was extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with brine (3×20 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the pure product was obtained by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (overall yield: 60-70%) (yield 77 mg).

MS m/z 596 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ 1.03-2.00 (m, 11H), 1.07 (t, 6H), 2.59 (q, 4H), 2.65 (t, 2H), 4.03 (t, 2H), 6.91 (d, 2H), 7.08 (d, 2H), 7.14 (s, 1H), 7.24-7.27 (m, 3H), 7.33 (d, 2H), 7.71 (d, 2H) ppm.

Example 418 [3-(4-{2-cyclohexyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (20 mmol), 4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt, solid potassium carbonate (60 mmol) was added, and the reaction mixture was heated to 90° C. for 5 h (monitored by TLC), according to General Procedure L1. After cooling to rt, the reaction mixture was poured into cold H₂O (60 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with H₂O (2×40 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo to afford the desired 1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude product was used directly for further transformation without further purification.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (50 mg) until completion as indicated by TLC or LC-MS, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline, which was used directly for further transformation without purification.

To a stirred solution of ice-cold 3-diethylaminopropanol (63 mmol) and TEA (80 mmol) dissolved in anhydrous DCM (50 mL) was added dropwise methanesulfonyl chloride (60 mmol), and the reaction mixture was stirred for 2 h at 0° C. and followed by additional 1 h at rt. After the removal of the solvents in vacuuo, the crude mesylate was dissolved in DMF (100 mL). 4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol) were added, and the mixture was heated with stirring at 90° C. for 18 h (monitored by LC-MS). After cooling to rt, the reaction was quenched with cold H₂O (100 mL), and the resulting mixture was extracted with EtOAc (4×100 mL). The combined EtOAc extracts were washed with brine (3×60 ml), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA.

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4 mmol) in MeOH (10 mL) at rt, pyrrolidone hydrotribromide (4.8 mmol) was added, according to General Procedure R1. The reaction mixture was stirred at it for 1 h (monitored by LC-MS). The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was directly used for further transformation.

To a stirred solution of 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline (4.8 mmol) dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added, followed by a slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained above (˜4 mmol), according to General Procedure R2. The reaction mixture was stirred at it and under nitrogen until completion (˜5 h), as indicated by LC-MS. The reaction was quenched with saturated sodium bicarbonate (50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with brine (3×40 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude product was purified by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA.

To a stirred solution of the alkylated aniline described above (0.2 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (1.2 mmol, 6 eq) was added, followed by a slow addition of cyclohexanecarbonyl chloride (0.6 mmol, 3 eq), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to it until completion, as indicated by LC-MS. The solvent was removed in vacuuo, and the crude amide was used directly for further transformation.

To a stirred solution of the amide described above (˜0.2 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜30 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 100° C. for 2-5 h (as monitored by LC-MS). The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate. The resulting mixture was extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with brine (3×20 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the pure product was obtained by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield 74 mg).

MS m/z 610 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ1.02-2.00 (m, 13H), 1.06 (t, 6H), 2.60 (q, 4H), 2.67 (t, 2H), 4.02 (t, 2H), 6.90 (d, 2H), 7.07 (d, 2H), 7.09 (s, 1H), 7.22-7.26 (m, 3H), 7.30 (d, 2H,), 7.69 (d, 2H) ppm.

Example 419 diethyl-[3-(4-{1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-propyl]-amine

To a stirred solution of 4-fluoronitrobenzene (20 mmol), 4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt, solid potassium carbonate (60 mmol) was added, and the reaction mixture was heated to 90° C. for 5 h (monitored by TLC), according to General Procedure L1. After cooling to rt, the reaction mixture was poured into cold H₂O (60 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with H₂O (2×40 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo to afford the desired 1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude product was used directly for further transformation without further purification.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (50 mg) until completion as indicated by TLC or LC-MS, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline, which was used directly for further transformation without purification (overall yield: 95%).

To a stirred solution of ice-cold 3-diethylaminopropanol (63 mmol) and TEA (80 mmol) dissolved in anhydrous DCM (50 mL) was added dropwise methanesulfonyl chloride (60 mmol), and the reaction mixture was stirred for 2 h at 0° C. and followed by additional 1 h at rt. After the removal of the solvents in vacuuo, the crude mesylate was dissolved in DMF (100 mL). 4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol) were added, and the mixture was heated with stirring at 90° C. for 18 h (monitored by LC-MS). After cooling to rt, the reaction was quenched with cold H₂O (100 mL), and the resulting mixture was extracted with EtOAc (4×100 mL). The combined EtOAc extracts were washed with brine (3×60 ml), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA.

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4 mmol) in MeOH (10 mL) at rt, pyrrolidone hydrotribromide (4.8 mmol) was added, according to General Procedure R1. The reaction mixture was stirred at it for 1 h (monitored by LC-MS). The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was directly used for further transformation.

To a stirred solution of 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline (4.8 mmol) dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added, followed by a slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained above (˜4 mmol), according to General Procedure R2. The reaction mixture was stirred at it and under nitrogen until completion (˜5 h), as indicated by LC-MS. The reaction was quenched with saturated sodium bicarbonate (50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with brine (3×40 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude product was purified by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA.

To a stirred solution of the alkylated aniline described above (0.2 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (1.2 mmol, 6 eq) was added, followed by a slow addition of isovaleryl chloride (0.6 mmol, 3 eq), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by LC-MS. The solvent was removed in vacuuo, and the crude amide was used directly for further transformation.

To a stirred solution of the amide described above (˜0.2 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜30 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 100° C. for 2-5 h (as monitored by LC-MS). The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate. The resulting mixture was extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with brine (3×20 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the pure product was obtained by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield 70 mg).

MS m/z 584 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ0.86 (d, 6H) 1.07 (t, 6H), 1.97 (m, 2H), 2.04 (m, 1H), 2.55 (d, 2H), 2.61 (q, 4H), 2.69 (t, 2H), 4.03 (t, 2H), 6.90 (d, 2H), 7.07 (d, 2H), 7.14 (s, 1H), 7.22-7.25 (m, 3H), 7.30 (d, 2H), 7.70 (d, 2H) ppm.

Example 420 [3-(4-{2-but-3-enyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (20 mmol), 4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt, solid potassium carbonate (60 mmol) was added, and the reaction mixture was heated to 90° C. for 5 h (monitored by TLC), according to General Procedure L1. After cooling to rt, the reaction mixture was poured into cold H₂O (60 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with H₂O (2×40 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo to afford the desired 1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude product was used directly for further transformation without further purification.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (50 mg) until completion as indicated by TLC or LC-MS, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline, which was used directly for further transformation without purification (overall yield: 95%).

To a stirred solution of ice-cold 3-diethylaminopropanol (63 mmol) and TEA (80 mmol) dissolved in anhydrous DCM (50 mL) was added dropwise methanesulfonyl chloride (60 mmol), and the reaction mixture was stirred for 2 h at 0° C. and followed by additional 1 h at rt. After the removal of the solvents in vacuuo, the crude mesylate was dissolved in DMF (100 mL). 4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol) were added, and the mixture was heated with stirring at 90° C. for 18 h (monitored by LC-MS). After cooling to rt, the reaction was quenched with cold H₂O (100 mL), and the resulting mixture was extracted with EtOAc (4×100 mL). The combined EtOAc extracts were washed with brine (3×60 ml), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield: 75%).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4 mmol) in MeOH (10 mL) at rt, pyrrolidone hydrotribromide (4.8 mmol) was added, according to General Procedure R1. The reaction mixture was stirred at rt for 1 h (monitored by LC-MS). The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was directly used for further transformation.

To a stirred solution of 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline (4.8 mmol) dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added, followed by a slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained above (˜4 mmol), according to General Procedure R2. The reaction mixture was stirred at rt and under nitrogen until completion (˜5 h), as indicated by LC-MS. The reaction was quenched with saturated sodium bicarbonate (50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with brine (3×40 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude product was purified by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield: 64%).

To a stirred solution of the alkylated aniline described above (0.2 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (1.2 mmol, 6 eq) was added, followed by a slow addition of pent-4-enoyl chloride (0.6 mmol, 3 eq), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by LC-MS. The solvent was removed in vacuuo, and the crude amide was used directly for further transformation.

To a stirred solution of the amide described above (˜0.2 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜30 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 100° C. for 2-5 h (as monitored by LC-MS). The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate. The resulting mixture was extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with brine (3×20 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the pure product was obtained by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield 58 mg).

MS m/z 582+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ 1.12 (t, 6H), 2.03 (m, 2H), 2.45 (t, 2H), 2.63 (t, 2H,), 2.73 (q, 4H), 2.77 (t, 2H), 4.04 (t, 2H), 4.94 (dd, 1H), 5.00 (dd, 1H), 5.79 (m, 1H), 6.90 (d, 2H), 7.07 (d, 2H), 7.15 (s, 1H), 7.24-7.25 (m, 3H), 7.32 (d, 2H, 7.70 (d, 2H) ppm.

Example 421 [3-(4-{2-tert-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (20 mmol), 4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt, solid potassium carbonate (60 mmol) was added, and the reaction mixture was heated to 90° C. for 5 h (monitored by TLC), according to General Procedure L1. After cooling to rt, the reaction mixture was poured into cold H₂O (60 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with H₂O (2×40 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo to afford the desired 1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude product was used directly for further transformation without further purification.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (50 mg) until completion as indicated by TLC or LC-MS, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline, which was used directly for further transformation without purification (overall yield: 95%).

To a stirred solution of ice-cold 3-diethylaminopropanol (63 mmol) and TEA (80 mmol) dissolved in anhydrous DCM (50 mL) was added dropwise methanesulfonyl chloride (60 mmol), and the reaction mixture was stirred for 2 h at 0° C. and followed by additional 1 h at rt. After the removal of the solvents in vacuuo, the crude mesylate was dissolved in DMF (100 mL). 4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol) were added, and the mixture was heated with stirring at 90° C. for 18 h (monitored by LC-MS). After cooling to rt, the reaction was quenched with cold H₂O (100 mL), and the resulting mixture was extracted with EtOAc (4×100 mL). The combined EtOAc extracts were washed with brine (3×60 ml), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA.

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4 mmol) in MeOH (10 mL) at rt, pyrrolidone hydrotribromide (4.8 mmol) was added, according to General Procedure R1. The reaction mixture was stirred at rt for 1 h (monitored by LC-MS). The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was directly used for further transformation.

To a stirred solution of 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline (4.8 mmol) dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added, followed by a slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained above (˜4 mmol), according to General Procedure R2. The reaction mixture was stirred at rt and under nitrogen until completion (˜5 h), as indicated by LC-MS. The reaction was quenched with saturated sodium bicarbonate (50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with brine (3×40 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude product was purified by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA.

To a stirred solution of the alkylated aniline described above (0.2 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (1.2 mmol, 6 eq) was added, followed by a slow addition of pivaloyl chloride (0.6 mmol, 3 eq), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by LC-MS. The solvent was removed in vacuuo, and the crude amide was used directly for further transformation.

To a stirred solution of the amide described above (˜0.2 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜30 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 100° C. for 2-5 h (as monitored by LC-MS). The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate. The resulting mixture was extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with brine (3×20 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the pure product was obtained by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield 76 mg).

MS m/z 584 (M+H)⁺

¹H NMR (400 MHz, CDCl₃): δ1.09 (t, 6H), 1.24 (s, 9H), 1.99 (m, 2H), 2.64 (q, 4H), 2.72 (t, 2H), 4.02 (t, 2H), 6.89 (d, 2H), 7.02 (s, 1H), 7.03 (d, 2H), 7.23-7.25 (m, 3H), 7.35 (d, 2H), 7.69 (d, 2H) ppm.

Example 422 diethyl-[3-(4-{2-(4-fluoro-phenyl)-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-amine

To a stirred solution of 4-fluoronitrobenzene (20 mmol), 4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt, solid potassium carbonate (60 mmol) was added, and the reaction mixture was heated to 90° C. for 5 h (monitored by TLC), according to General Procedure L1. After cooling to rt, the reaction mixture was poured into cold H₂O (60 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with H₂O (2×40 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo to afford the desired 1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude product was used directly for further transformation without further purification.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (50 mg) until completion as indicated by TLC or LC-MS, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline, which was used directly for further transformation without purification (overall yield: 95%).

To a stirred solution of ice-cold 3-diethylaminopropanol (63 mmol) and TEA (80 mmol) dissolved in anhydrous DCM (50 mL) was added dropwise methanesulfonyl chloride (60 mmol), and the reaction mixture was stirred for 2 h at 0° C. and followed by additional 1 h at rt. After the removal of the solvents in vacuuo, the crude mesylate was dissolved in DMF (100 mL). 4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol) were added, and the mixture was heated with stirring at 90° C. for 18 h (monitored by LC-MS). After cooling to rt, the reaction was quenched with cold H₂O (100 mL), and the resulting mixture was extracted with EtOAc (4×100 mL). The combined EtOAc extracts were washed with brine (3×60 ml), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield: 75%).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4 mmol) in MeOH (10 mL) at rt, pyrrolidone hydrotribromide (4.8 mmol) was added, according to General Procedure R1. The reaction mixture was stirred at rt for 1 h (monitored by LC-MS). The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was directly used for further transformation.

To a stirred solution of 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline (4.8 mmol) dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added, followed by a slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained above (˜4 mmol), according to General Procedure R2. The reaction mixture was stirred at rt and under nitrogen until completion (˜5 h), as indicated by LC-MS. The reaction was quenched with saturated sodium bicarbonate (50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with brine (3×40 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude product was purified by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield: 64%).

To a stirred solution of the alkylated aniline described above (0.2 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (1.2 mmol, 6 eq) was added, followed by a slow addition of 4-fluorobenzoyl chloride (0.6 mmol, 3 eq), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by LC-MS. The solvent was removed in vacuuo, and the crude amide was used directly for further transformation.

To a stirred solution of the amide described above (˜0.2 mmol) in acetic acid (2 mL), ammonium acetate (excess, -30 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 100° C. for 2-5 h (as monitored by LC-MS). The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate. The resulting mixture was extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with brine (3×20 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the pure product was obtained by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (overall yield: 60-70%) (yield 75 mg).

MS m/z 622 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ1.11 (t, 6H), 2.01 (m, 2H), 2.67 (q, 4H), 2.75 (t, 2H), 4.05 (t, 2H), 6.93 (d, 2H), 6.98-7.26 (m, 7H), 7.01 (d, 2H), 7.33 (s, 1H), 7.43 (d, 2H), 7.44 (d, 1H), 7.78 (d, 2H) ppm.

Example 423 [3-(4-{1-[4-(3,5-bis-trifluoromethyl-phenoxy)-phenyl]-2-butyl-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM (25 mL), TEA (40 mmol, 2 eq) was added and the mixture was cooled to 0° C. To this mixture, methanesulfonyl chloride (30 mmol, 1.5 eq) was added slowly with stirring and the reaction mixture was stirred at 0° C. for an hour and at rt for another hour (until the reaction was complete by HPLC). The solvent was removed and saturated aqueous sodium bicarbonate was added. The product was extracted with EtOAc (3×) and washed with sodium bicarbonate and water. The solvent was removed in vacuuo.

The mesylate from the previous step (20 mmol, 1 eq) was dissolved in anhydrous DMF (25 mL) to which 4-hydroxyacetophenone (20 mmol, 1 eq) and potassium carbonate (60 mmol, 3 eq) were added. The mixture was heated under reflux at 85° C. for 18 h (until the reaction was complete by HPLC), after which it was cooled to rt. Saturated aqueous sodium bicarbonate was added to the mixture, which was then transferred to a separatory funnel. The product was extracted with EtOAc and washed with sodium bicarbonate and water. The solvent was removed in vacuuo and the 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by flash chromatography (going by increasing gradient up to 10% MeOH in DCM). The overall yield was 60%.

3,5-bis-trifluoromethylphenol (10 mmol) was dissolved in 15 ml of anhydrous DMF and potassium carbonate (30 mmol) was added with stirring at rt. 4-Fluoronitrobenzene (10 mmol) was added to this mixture, which was then heated under reflux at 80° C. for 18 h. The reaction was quenched with 30 ml of water and 30 ml of sodium bicarbonate, extracted with EtOAc (3×50 ml) and washed with sodium bicarbonate and water. The EtOAc layer was dried over anhydrous sodium sulfate and filtered, after which the solvent was removed in vacuuo.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOH (30 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-(3,5-bis-trifluoromethyl)phenoxyaniline, which was used directly for further transformation without further purification (yield 80%).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (6 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a solution of 4-(3,5-bis-trifluoromethyl)phenoxyaniline (1 eq, 2 mmol) in anhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was added, followed by addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (2 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Removal of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product obtained from 2-4% MeOH/DCM (yield 50%).

To a stirred solution of alkylated aniline described above (1 mmol) in anhydrous DCM (4 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed by a slow addition of valeryl chloride (3 eq, 3 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1 mmol) in acetic acid (4 mL), ammonium acetate (20 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield 139 mg).

MS m/z 635 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ 7.7 (d, 2H), 7.3 (m, 3H), 7.1 (m, 5H), 6.9 (d, 2H), 4.0 (t, 2H), 2.6-2.8 (m, 8H), 2.0 (m, 2H), 1.6 (m, 2H), 1.3 (m, 2H), 1.1 (t, 6H), 0.8 (t, 3H) ppm.

Example 424 (3-{4-[1-(4-benzyloxy-phenyl)-2-butyl-1H-imidazol-4-yl]-phenoxy}-propyl)-diethyl-amine

3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM (25 mL), TEA (40 mmol, 2 eq) was added and the mixture was cooled to 0° C. To this mixture, methanesulfonyl chloride (30 mmol, 1.5 eq) was added slowly with stirring and the reaction mixture was stirred at 0° C. for an hour and at it for another hour (until the reaction was complete by HPLC). The solvent was removed and saturated aqueous sodium bicarbonate was added. The product was extracted with EtOAc (3×) and washed with sodium bicarbonate and water. The solvent was removed in vacuuo.

The mesylate from the previous step (20 mmol, 1 eq) was dissolved in anhydrous DMF (25 mL) to which 4-hydroxyacetophenone (20 mmol, 1 eq) and potassium carbonate (60 mmol, 3 eq) were added. The mixture was heated under reflux at 85° C. for 18 h (until the reaction was complete by HPLC), after which it was cooled to rt. Saturated aqueous sodium bicarbonate was added to the mixture, which was then transferred to a separatory funnel. The product was extracted with EtOAc and washed with sodium bicarbonate and water. The solvent was removed in vacuuo and the product was purified by flash chromatography (going by increasing gradient up to 10% MeOH in DCM). The overall yield was 60%.

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (6 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to it until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a solution of 4-benzyloxyaniline (1 eq, 2 mmol) in anhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was added, followed by addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (2 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at it until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product obtained from 2-4% MeOH/DCM (yield 56%).

To a stirred solution of alkylated aniline described above (1 mmol) in anhydrous DCM (4 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed by a slow addition of valeryl chloride (3 eq, 3 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to it until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1 mmol) in acetic acid (4 mL), ammonium acetate (20 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield 205 mg).

MS m/z 513 (M+H)⁺;

¹H NMR (CDCl₃): δ 7.68 (d, 2H), 7.40 (m, 5H), 7.23 (d, 2H), 7.11 (s, 1H), 7.05 (d, 2H), 6.89 (d, 2H), 5.12 (s, 2H), 4.02 (t, 2H), 2.62-2.73 (m, 8H), 1.98 (m, 2H), 1.63 (m, 2H), 1.28 (m, 2H), 1.07 (t, 6H), 0.82 (t, 3H) ppm.

Example 425 {3-[4-(2-tert-butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide (2.2 mmol) in THF was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crude product was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-alkoxyaniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched using cold water (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated acetophenone was used for further transformation.

To a stirred solution of the 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the residue was treated with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by chromatography (Silica gel). Pure product was obtained from 20-30% EtOAc/hexane (yield ˜70-75%).

To a stirred solution of the N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (1.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of 1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 4.8 mmol) was added, followed by slow addition of pivaloyl chloride (2 eq., 3.2 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in DCM. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in acetic acid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield: 270 mg).

MS m/z 561 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.69 (d, 2H), 7.23-7.25 (m, 6H), 6.98 (s, 1H), 6.84 (m 4H), 4.15 (t, 2H), 4.08 (t, 2H), 3.05 (t, 2H), 2.85 (m, 6H), 2.16 (s, 9H), 2.05 (m, 2H), 1.19 (t, 6H) ppm.

Example 426 [3-(4-{2-butyl-1-[4-(3-fluoro-4-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 4-benzyloxyacetophenone (7.0 mmol) in anhydrous DCM (30.0 mL) and MeOH (5.0 mL) at rt, pyridinium bromide perbromide (1.1 eq.) was added. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC. The mixture was diluted with EtOAc (100 ml) and washed with H₂O (2×50 ml), brine (30 ml) and dried with magnesium sulfate. The solvent was then removed in vacuuo to give a white solid. The alpha-bromoacetophenone was used for further transformation without further purification.

To a stirred solution of 4-(3-fluoro-4-trifluoromethyl-phenoxy)-aniline (1.64 mmol) in anhydrous DMF (30 mL) DIEA (3 eq) was added, followed by slow addition of the alpha-bromoacetophenone described above (2 eq), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC and HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in Et₂O. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained from 5-20% EtOAc/Hexane (yield ˜50-60%).

To a stirred solution of alkylated aniline described above (1.0 mmol) in anhydrous THF (20 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed by slow addition of valeryl chloride (3 eq, 3.0 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to ambient temperature until completion, as indicated by TLC and HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.0 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 5-15% EtOAc/Hexane (yield 80%). (MS: m/z 562 (M+H)⁺)

The above product was dissolved in MeOH (20 mL), and Pd/C (100 mg) was added and the heterogeneous mixture was stirred overnight under hydrogen atmosphere using a balloon, according to General Procedure H. The Pd/C was removed by filtration. The solvent was removed in vacuuo, and the crude phenol (MS: m/z 472 (M+H)⁺) was used for further transformation.

To a stirred solution of the phenol (1.0 eq) obtained above in anhydrous DMF (5.0 mL) solid sodium hydride (60% dispersion in oil; 1.0 mmol) was added in portions. After the addition, the requisite alkylhalide or the mesylate (prepared from the corresponding alcohol and methanesulfonyl chloride) (1.5-2.0 eq) was added to the reaction mixture. The reaction mixture was heated at 90° C. overnight. After cooling the mix to rt, Et₂O (30 mL) was added to the reaction mixture followed by H₂O (10 mL). The organic layer was washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. The solvent was removed in vacuuo. Pure product was obtained from 5-10% MeOH/DCM (yield 65.0 mg).

MS m/z 557 (M+H)⁺:

¹H NMR (CDCl₃): δ 7.70 (d, 2H), 7.20-7.35 (m, 5H), 7.14 (s, 1H), 7.08 (d, 2H), 6.92 (d, 2H), 4.02 (t, 2H), 2.66 (t, 2H), 2.47 (t, 2H), 2.26 (s, 6H), 1.96 (m, 2H), 1.64 (m, 2H), 1.29 (m, 2H) 0.9 (t, 3H) ppm.

Example 427 diethyl-[3-(4-{4-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-amine

To a stirred solution of N-[3-(4-aminophenoxy)propyl]-N,N-diethylamine (1.2 eq, 2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq 6 mmol) was added, followed by a slow addition of 2-bromo-1-(4-bromophenyl)ethanone (1.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained from 2-4% MeOH/DCM (yield ˜50-60%).

To a stirred solution of 1-(4-bromophenyl)-2-({4-[3-(diethylamino)propoxy]phenyl}amino)ethanone (2 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield 40-50%).

To a solution of N-(3-{4-[4-(4-bromophenyl)-1H-imidazol-1-yl]phenoxy}propyl)-N,N-diethylamine (0.07 mmol) in pyridine (1 mL), copper powder was added (0.14 mmol), followed by potassium carbonate (0.35 mmol) and 4-fluoro-3-methylphenol (0.14 mmol). The mixture was heated at 110° C. overnight, then diluted with H₂O (2 mL) and extracted with EtOAc (3×2 mL). The combined organic extract was dried over sodium sulfate, filtered and concentrated to an oil, which was purified by column chromatography (Silica gel). The pure product was obtained from 1-6% MeOH/DCM.

MS m/z 528 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ 7.86-7.78 (m, 3H), 7.54-7.44 (m, 2H), 7.38-7.34 (m, 2H), 7.28-7.24 (m, 1H), 7.20-7.16 (m, 2H), 7.06-6.80 (m, 3H), 4.10 (t, 2H), 2.80-2-60 (m, 6H), 2.10-2.00 (m, 2H), 1.30 (t, 3H), 1.10 (t, 3H) ppm.

Example 428 (3-{4-[4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-(4-fluoro-phenyl)-imidazol-1-yl]-phenoxy}-propyl)-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide (2.2 mmol) in THF was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. for 1 h and allowed to warm to it until completion, as indicated by TLC or HPLC. The reaction mixture was then treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crude product was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-alkoxyaniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched using cold water (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated acetophenone was used for further transformation.

To a stirred solution of the 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the residue was treated with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by chromatography (Silica gel). Pure product was obtained from 20-30% EtOAc/hexane (yield ˜70-75%).

To a stirred solution of the N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (1.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of 1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 4.8 mmol) was added, followed by slow addition of 4-fluorobenzoyl chloride (2 eq., 3.2 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in DCM. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in acetic acid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield: 334 mg).

MS m/z 598 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.76 (d, 2H), 7.41 (m, 2H), 7.26 (m, 2H), 7.21 (d, 2H), 7.16 (d, 2H), 7.01 (m, 7H), 4.16 (t, 2H), 4.05 (t, 2H), 3.05 (t, 2H), 2.97 (m, 6H), 2.18 (m, 2H), 1.24 (t, 6H) ppm

Example 429 {3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-cyclopropyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide (2.2 mmol) in THF was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crude product was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-alkoxyaniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched using cold water (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated acetophenone was used for further transformation.

To a stirred solution of the 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the residue was treated with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by chromatography (Silica gel). Pure product was obtained from 20-30% EtOAc/hexane.

To a stirred solution of the N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (1.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of 1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 4.8 mmol) was added, followed by slow addition of cyclopropanecarbonyl chloride (2 eq., 3.2 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in DCM. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in acetic acid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield: 260 mg).

MS m/z 544 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.65 (d, 2H), 7.31 (m, 4H), 7.21 (d, 2H), 7.18 (s, 1H), 6.98 (d, 2H), 6.88 (d 2H), 4.18 (t, 2H), 4.08 (t, 2H), 3.07 (t, 2H), 3.12 (m, 1H) 2.78 (m, 6H), 2.57 (m, 4H), 2.06 (m, 2H), 1.12 (t, 6H) ppm

Example 430 {3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-cyclopentyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide (2.2 mmol) in THF was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crude product was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-alkoxyaniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched using cold water (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated acetophenone was used for further transformation.

To a stirred solution of the 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the residue was treated with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by chromatography (Silica gel). Pure product was obtained from 20-30% EtOAc/hexane (yield ˜70-75%).

To a stirred solution of the N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (1.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of 1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 4.8 mmol) was added, followed by slow addition of cyclopentanecarbonyl chloride (2 eq., 3.2 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in DCM. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in acetic acid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to it and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield: 366 mg).

MS m/z 572 (M+H)⁺:

Example 431 [3-(4-{4-[4-(biphenyl-4-yloxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of N-[3-(4-aminophenoxy)propyl]-N,N-diethylamine (1.2 eq, 2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq 6 mmol) was added, followed by a slow addition of the 2-bromo-1-(4-bromophenyl)ethanone described above (1.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained from 2-4% MeOH/DCM (yield ˜50-60%).

To a stirred solution of 1-(4-bromophenyl)-2-({4-[3-(diethylamino)propoxy]phenyl}amino)ethanone (2 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield 40-50%).

To a solution of the N-(3-{4-[4-(4-bromophenyl)-1H-imidazol-1-yl]phenoxy}propyl)-N,N-diethylamine (0.07 mmol) in pyridine (1 mL), copper powder was added (0.14 mmol), followed by potassium carbonate (0.35 mmol) and 1,1′-biphenyl-4-ol (0.14 mmol). The mixture was heated at 110° C. overnight, then diluted with H₂O (2 mL) and extracted with EtOAc (3×2 mL). The combined organic extract was dried over sodium sulfate, filtered and concentrated to an oil, which was purified by column chromatography (Silica gel). The pure product was obtained from 1-6% MeOH/DCM (yield 11 mg).

MS m/z 518 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ 7.83-7.79 (m, 3H), 7.59-7.57 (m, 4H), 7.45-7.43 (m, 4H), 7.42-7.34 (m, 4H), 7.11 (d, 2H), 7.05 (d, 3H), 4.10 (t, 2H), 2.80-2-60 (m, 6H), 2.00-2.10 (m, 2H), 1.30 (t, 3H), 1.10 (t, 3H) ppm.

Example 432 diethyl-[3-(4-{4-[4-(3-trifluoromethyl-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-amine

To a stirred solution of N-[3-(4-aminophenoxy)propyl]-N,N-diethylamine (1.2 eq, 2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq 6 mmol) was added, followed by a slow addition of 2-bromo-1-(4-bromophenyl)ethanone (1.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained from 2-4% MeOH/DCM (yield ˜50-60%).

To a stirred solution of 1-(4-bromophenyl)-2-({4-[3-(diethylamino)propoxy]phenyl}amino)ethanone (2 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq) was added, according to General Procedure R4.

The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield 40-50%).

To a solution of N-(3-{4-[4-(4-bromophenyl)-1H-imidazol-1-yl]phenoxy}propyl)-N,N-diethylamine (0.07 mmol) in pyridine (1 mL), copper powder was added (0.14 mmol), followed by potassium carbonate (0.35 mmol) and 3-(trifluoromethyl)phenol (0.14 mmol). The mixture was heated at 110° C. overnight, then diluted with H₂O (2 mL) and extracted with EtOAc (3×2 mL). The combined organic extract was dried over sodium sulfate, filtered and concentrated to an oil, which was purified by column chromatography (Silica gel). The pure product was obtained from 1-6% MeOH/DCM (yield 10 mg).

MS m/z 510 (M+H)⁺:

Example 433 [3-(4-{4-[4-(3,4-dichloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of N-[3-(4-aminophenoxy)propyl]-N,N-diethylamine (1.2 eq, 2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq 6 mmol) was added, followed by a slow addition of 2-bromo-1-(4-bromophenyl)ethanone (1.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained from 2-4% MeOH/DCM (yield ˜50-60%).

To a stirred solution of 1-(4-bromophenyl)-2-({4-[3-(diethylamino)propoxy]phenyl}amino)ethanone (2 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield 40-50%).

To a solution of N-(3-{4-[4-(4-bromophenyl)-1H-imidazol-1-yl]phenoxy}propyl)-N,N-diethylamine (0.07 mmol) in pyridine (1 mL), copper powder was added (0.14 mmol) followed by potassium carbonate (0.35 mmol), and 3,4-dichlorophenol (0.14 mmol). The mixture was heated at 110° C. overnight, then diluted with H₂O (2 mL) and extracted with EtOAc (3×2 mL). The combined organic extract was dried over sodium sulfate, filtered and concentrated to an oil, which was purified by column chromatography (Silica gel). The pure product was obtained from 1-6% MeOH/DCM (yield 15 mg).

MS m/z 510 (M+H)⁺:

Example 434 [3-(4-{2-butyl-1-[4-(4-methoxy-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM (25 mL), TEA (40 mmol, 2 eq) was added and the mixture was cooled to 0° C. To this mixture, methanesulfonyl chloride (30 mmol, 1.5 eq) was added slowly with stirring and the reaction mixture was stirred at 0° C. for an hour and at rt for another hour (until the reaction was complete by HPLC). The solvent was removed and to this saturated aqueous sodium bicarbonate was added. The product was extracted with EtOAc (3×) and washed with sodium bicarbonate and water. The solvent was removed in vacuuo.

The mesylate from the previous step (20 mmol, 1 eq) was dissolved in anhydrous DMF (25 mL) to which 4-hydroxyacetophenone (20 mmol, 1 eq) and potassium carbonate (60 mmol, 3 eq) were added. The mixture was heated under reflux at 85° C. for 18 h (until the reaction was complete by HPLC), after which it was cooled to rt. Saturated aqueous sodium bicarbonate was added to the mixture, which was then transferred to a separatory funnel. The product was extracted with EtOAc and washed with sodium bicarbonate and water. The solvent was removed in vacuuo and the 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by flash chromatography (going by increasing gradient up to 10% MeOH in DCM). The overall yield was 60%.

4-Methoxyphenol (10 mmol) was dissolved in 15 ml of anhydrous DMF and potassium carbonate (30 mmol) was added with stirring at rt. 4-Fluoronitrobenzene (10 mmol) was added to this mixture, which was then heated under reflux at 80° C. for 18 h. The reaction was quenched with 30 ml of water and 30 ml of sodium bicarbonate, extracted with EtOAc (3×50 ml) and washed with sodium bicarbonate and water. The EtOAc layer was dried over anhydrous sodium sulfate and filtered, after which the solvent was removed in vacuuo.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOH (30 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-(4-methoxyphenoxy)aniline, which was used directly for further transformation without further purification (yield 80%).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (6 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a solution of 4-(4-methoxyphenoxy) aniline (1 eq, 2 mmol) in anhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was added, followed by addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (2 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product obtained from 2-4% MeOH/DCM (yield 52%).

To a stirred solution of alkylated aniline described above (1 mmol) in anhydrous DCM (4 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed by a slow addition of valeryl chloride (3 eq, 3 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1 mmol) in acetic acid (4 mL), ammonium acetate (20 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield 190 mg).

MS m/z 529 (M+H)⁺:

¹H NMR (CDCl₃): δ7.7 (d, 2H), 7.2 (d, 2H), 7.16 (s, 1H), 6.8-7.1 (m, 8H), 4.0 (t, 2H), 3.8 (s, 3H), 2.8-3.0 (m, 8H), 2.6 (m, 2H), 2.2 (m, 2H), 1.6 (m, 2H), 1.2 (t, 6H), 0.8 (t, 3H) ppm.

Example 435 1-[2-(4-{2-butyl-1-[4-(3-fluoro-4-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-ethyl]-piperazine

To a stirred solution of 4-benzyloxyacetophenone (7.0 mmol) in anhydrous DCM (30.0 mL) and MeOH (5.0 mL) at rt, pyridinium bromide perbromide (1.1 eq.) was added. The reaction mixture was stirred under nitrogen at it until completion, as indicated by TLC. The mixture was diluted with EtOAc (100 ml) and washed with H₂O (2×50 ml), brine (30 ml) and dried with magnesium sulfate. The solvent was then removed in vacuuo to give a white solid. The alpha-bromoacetophenone was used for further transformation without further purification.

To a stirred solution of 4-(3-fluoro-4-trifluoromethyl-phenoxy)-aniline (1.64 mmol) in anhydrous DMF (30 mL) DIEA (3 eq) was added, followed by slow addition of the alpha-bromoacetophenone described above (2 eq), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC and HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in Et₂O. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained from 5-20% EtOAc/Hexane (yield ˜50-60%).

To a stirred solution of alkylated aniline described above (1.0 mmol) in anhydrous THF (20 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed by slow addition of valeryl chloride (3 eq, 3.0 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to ambient temperature until completion, as indicated by TLC and HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.0 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 5-15% EtOAc/Hexane (yield 80%).

(MS: m/z 562 (M+H)⁺)

The above product was dissolved in MeOH (20 mL), and Pd/C (100 mg) was added and the heterogeneous mixture was stirred overnight under hydrogen atmosphere using a balloon, according to General Procedure H. The Pd/C was removed by filtration. The solvent was removed in vacuuo, and the crude phenol (MS: m/z 472 (M+H)⁺) was used for further transformation.

To a stirred solution of the phenol (0.16 mmol) obtained above in anhydrous DMF (5 mL) solid sodium hydride (60% dispersion in oil; 1.0 mmol) was added in portions. After the addition, 4-(2-methanesulfonyloxy)-piperazine-1-carboxylic acid tertbutylester (2.0 mmol) was added to the reaction mixture. The reaction mixture was heated at 90° C. overnight. After cooling the mix to rt, Et₂O (30 mL) was added to the reaction mixture followed by H₂O (10 mL). The organic layer was washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. The solvent was removed in vacuuo. Pure product was obtained from 5-10% MeOH/DCM (yield ˜45%).

This product was dissolved in DCM (10 mL) and HCl (4.0 M in dioxane, 1.0 mL) was added and stirrings continued overnight until reaction completed as indicated by HPLC. EtOAc (40 ml) added, followed by sodium bicarbonate (sat, 15 mL). The organic layer was washed with brine (10 mL) and dried with magnesium sulfate. The solvent was removed in in vacuuo to give the title compound as white solid (yield 37 mg).

MS m/z 584 (M+H)⁺:

¹H NMR (CDCl₃): δ7.70 (d, 2H), 7.20-7.35 (m, 5H), 7.14 (s, 1H), 7.08 (d, 2H), 6.92 (d, 2H), 4.05 (t, 2H), 3.0 (m, 4H), 2.8 (t, 2H), 3.4 (m, 6H), 1.6 (m, 2H), 1.3 (m, 3H), 0.9 (t, 3H) ppm.

Example 436 {3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-propyl}-dimethyl-amine

To a stirred solution of 4-aminophenol (4.8 mmol) in MeOH (20 mL), 1-bromo-4′-(4-chlorophenethoxy)acetophenone (4 mmol) was added at rt. The resulting mixture was then heated to reflux for 45 min. The reaction mixture was then cooled to rt and the solvent was removed in vacuuo. The resulting solid was dissolved in EtOAc (30 mL), washed with H₂O (2×20 mL) and brine (20 mL) and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired 1-(4-hydroxyphenyl)amino-4′-(4-chlorophenethoxy)acetophenone, which was used for further transformation.

The aminoacetophenone obtained as above (3 mmol) was dissolved in formic acid (3 mL) and added with ammonium formate (60 mmol). The resulting mixture was heated to 90° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product, 4-{4-[2-(4-chlorophenyl)ethoxy]phenyl}-1-[(4-hydroxy)phenyl]-1H-imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield ˜50%).

To a solution of the product obtained above (0.5 mmol) in anhydrous THF (2 mL), NaH (60% dispersion in oil; 1 mmol) was added at 0° C. The resuting mixture was added with a solution of the mesylate of N,N-dimethylpropanol (0.6 mmol) in THF (1 mL). The reaction mixture was then heated to 70° C. overnight. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM.

MS m/z 476 (M+H)⁺:

¹H NMR (CDCl₃): δ7.76 (s, 1H), 7.73 (d, 2H), 7.38 (s, 1H), 7.31 (d, 2H), 7.25 (AB_(q), 4H), 6.99 (d, 2H), 6.92 (d, 2H,), 4.18 (t, 2H), 4.05 (t, 2H), 3.07 (t, 2H), 2.49 (t, 2H), 2.28 (s, 6H), 1.99 (q, 2H) ppm.

Example 437 4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-1-{4-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-1H-imidazole

To a stirred solution of 4-aminophenol (4.8 mmol) in MeOH (20 mL), 1-bromo-4′-(4-chlorophenethoxy)acetophenone (4 mmol) was added at rt. The resulting mixture was then heated to reflux for 45 min. The reaction mixture was then cooled to rt and the solvent was removed in vacuuo. The resulting solid was dissolved in EtOAc (30 mL), washed with H₂O (2×20 mL) and brine (20 mL) and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired 1-(4-hydroxyphenyl)amino-4′-(4-chlorophenethoxy)acetophenone, which was used for further transformation.

The aminoacetophenone obtained as above (3 mmol) was dissolved in formic acid (3 mL) and added with ammonium formate (60 mmol). The resulting mixture was heated to 90° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product, 4-{4-[2-(4-chlorophenyl)ethoxy]phenyl}-1-[(4-hydroxy)phenyl]-1H-imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield ˜50%).

To a solution of the product obtained above (0.5 mmol) in anhydrous THF (2 mL), NaH (60% dispersion in oil; 1 mmol) was added at 0° C. The resuting mixture was added with a solution of the mesylate of 2-(N-methylpyrrolidin-2-yl)ethanol (0.6 mmol) in THF (1 mL). The reaction mixture was then heated to 70° C. overnight. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was by obtained by elution with 4-6% MeOH/DCM (yield 125 mg).

MS m/z 503 (M+H)⁺:

¹H NMR (CDCl₃): δ7.75 (s, 1H), 7.72 (d, 2H), 7.38 (s, 1H), 7.31 (d, 2H), 7.26 (AB_(q), 4H), 6.95 (d, 2H), 6.92 (d, 2H), 4.17 (t, 2H), 3.04 (t, 2H), 2.90-2.50 (m, 4H), 2.43 (s, 3H), 2.30-1.50 (m, 7H) ppm.

Example 438 1-{2-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-ethyl}-piperazine

To a stirred solution of 4-aminophenol (4.8 mmol) in MeOH (20 mL), 1-bromo-4′-(4-chlorophenethoxy)acetophenone (4 mmol) was added at rt. The resulting mixture was then heated to reflux for 45 min. The reaction mixture was then cooled to rt and the solvent was removed in vacuuo. The resulting solid was dissolved in EtOAc (30 mL), washed with H₂O (2×20 mL) and brine (20 mL) and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired 1-(4-hydroxyphenyl)amino-4′-(4-chlorophenethoxy)acetophenone, which was used for further transformation.

The aminoacetophenone obtained as above (3 mmol) was dissolved in formic acid (3 mL) and added with ammonium formate (60 mmol). The resulting mixture was heated to 90° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product, 4-{4-[2-(4-chlorophenyl)ethoxy]phenyl}-1-[(4-hydroxy)phenyl]-1H-imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained by elution with 4-6% MeOH/DCM (yield ˜50%).

To a solution of the product obtained above (0.5 mmol) in anhydrous THF (2 mL), NaH (60% dispersion in oil; 1 mmol) was added at 0° C. The resuting mixture was added with a solution of the mesylate of 1-(t-butyloxycarbonyl)-2-(2-hydroxy)ethylpiperazine (0.6 mmol) in THF (1 mL). The reaction mixture was then heated to 70° C. overnight. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained by elution with 4-6% MeOH/DCM (yield ˜50%).

The product obtained above was treated with 4M HCl in dioxane (1 mL) and the resulting mixture was stirred at rt for 4 h. Evaporation of the solvent, repeated washing of the hydrochloride salt thus obtained with diethyl ether and subsequent drying in vacuuo afforded the desired product.

MS m/z 503 (M+H)⁺:

¹H NMR (CD₃OD): δ9.47 (s, 1H), 8.28 (s, 1H), 7.76 (d, 2H), 7.72 (d, 2H), 7.33 (d, 2H), 7.29 (s, 4H), 7.06 (d, 2H), 4.58 (broad t, 2H), 4.22 (t, 2H), 3.83 (broad t, 4H), 3.74 (broad t, 6H), 3.06 (t, 2H) ppm.

Example 439 [3-(4-{2-(3-cyclohexyl-propyl)-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (20 mmol), 4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt, solid potassium carbonate (60 mmol) was added, and the reaction mixture was heated to 90° C. for 5 h (monitored by TLC), according to General Procedure L1. After cooling to rt, the reaction mixture was poured into cold H₂O (60 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with H₂O (2×40 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo to afford the desired 1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude product was used directly for further transformation without further purification.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (50 mg) until completion as indicated by TLC or LC-MS, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline, which was used directly for further transformation without purification (overall yield: 95%).

To a stirred solution of ice-cold 3-diethylaminopropanol (63 mmol) and TEA (80 mmol) dissolved in anhydrous DCM (50 mL) was added dropwise methanesulfonyl chloride (60 mmol), and the reaction mixture was stirred for 2 h at 0° C. and followed by additional 1 h at rt. After the removal of the solvents in vacuuo, the crude mesylate was dissolved in DMF (100 mL). 4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol) were added, and the mixture was heated with stirring at 90° C. for 18 h (monitored by LC-MS). After cooling to rt, the reaction was quenched with cold H₂O (100 mL), and the resulting mixture was extracted with EtOAc (4×100 mL). The combined EtOAc extracts were washed with brine (3×60 ml), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield: 75%).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4 mmol) in MeOH (10 mL) at rt, pyrrolidone hydrotribromide (4.8 mmol) was added, according to General Procedure R1. The reaction mixture was stirred at it for 1 h (monitored by LC-MS). The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was directly used for further transformation.

To a stirred solution of 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline (4.8 mmol) dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added, followed by a slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained above (˜4 mmol), according to General Procedure R2. The reaction mixture was stirred at rt and under nitrogen until completion (˜5 h), as indicated by LC-MS. The reaction was quenched with saturated sodium bicarbonate (50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with brine (3×40 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude product was purified by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield: 64%).

To a stirred solution of the alkylated aniline described above (0.2 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (1.2 mmol, 6 eq) was added, followed by a slow addition of 4-cyclohexylbutanoyl chloride (0.6 mmol, 3 eq), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by LC-MS. The solvent was removed in vacuuo, and the crude amide was used directly for further transformation.

To a stirred solution of the amide described above (˜0.2 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜30 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 100° C. for 2-5 h (as monitored by LC-MS). The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate. The resulting mixture was extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with brine (3×20 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the pure product was obtained by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (overall yield: 60-70%) (yield 78 mg).

MS m/z 652 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ 0.75-1.65 (m, 15H), 1.07 (t, 6H), 1.97 (m, 2H), 2.62 (q, 4H), 2.63-2.70 (m, 4H), 4.02 (t, 2H), 6.90 (d, 2H), 7.07 (d, 2H), 7.14 (s, 1H), 7.22 (br s, 1H), 7.23 (br d, 1H), 7.25 (d, 1H), 7.31 (d, 2H), 7.69 (d, 2H) ppm.

Example 440 diethyl-(3-{4-[1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-2-(3-phenoxy-propyl)-1H-imidazol-4-yl]-phenoxy}-propyl)-amine

To a stirred solution of 4-fluoronitrobenzene (20 mmol), 4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt, solid potassium carbonate (60 mmol) was added, and the reaction mixture was heated to 90° C. for 5 h (monitored by TLC), according to General Procedure L1. After cooling to rt, the reaction mixture was poured into cold H₂O (60 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with H₂O (2×40 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo to afford the desired 1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude product was used directly for further transformation without further purification.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (50 mg) until completion as indicated by TLC or LC-MS, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline, which was used directly for further transformation without purification (overall yield: 95%).

To a stirred solution of ice-cold 3-diethylaminopropanol (63 mmol) and TEA (80 mmol) dissolved in anhydrous DCM (50 mL) was added dropwise methanesulfonyl chloride (60 mmol), and the reaction mixture was stirred for 2 h at 0° C. and followed by additional 1 h at rt. After the removal of the solvents in vacuuo, the crude mesylate was dissolved in DMF (100 mL). 4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol) were added, and the mixture was heated with stirring at 90° C. for 18 h (monitored by LC-MS). After cooling to rt, the reaction was quenched with cold H₂O (100 mL), and the resulting mixture was extracted with EtOAc (4×100 mL). The combined EtOAc extracts were washed with brine (3×60 ml), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield: 75%).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4 mmol) in MeOH (10 mL) at rt, pyrrolidone hydrotribromide (4.8 mmol) was added, according to General Procedure R1. The reaction mixture was stirred at rt for 1 h (monitored by LC-MS). The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was directly used for further transformation.

To a stirred solution of 4-(4′-fluoro-3′-trifluoromethyl-phenoxy)aniline (4.8 mmol) dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added, followed by a slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained above (˜4 mmol), according to General Procedure R2. The reaction mixture was stirred at rt and under nitrogen until completion (˜5 h), as indicated by LC-MS. The reaction was quenched with saturated sodium bicarbonate (50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with brine (3×40 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude product was purified by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield: 64%).

To a stirred solution of the alkylated aniline described above (0.2 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (1.2 mmol, 6 eq) was added, followed by a slow addition of 4-phenoxybutanoyl chloride (0.6 mmol, 3 eq), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by LC-MS. The solvent was removed in vacuuo, and the crude amide was used directly for further transformation.

To a stirred solution of the amide described above (˜0.2 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜30 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 100° C. for 2-5 h (as monitored by LC-MS). The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate. The resulting mixture was extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with brine (3×20 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the pure product was obtained by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield 73 mg).

MS m/z 662 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ1.06 (t, 6H), 1.97 (m, 2H), 2.24 (m, 2H), 2.60 (q, 4H), 2.67 (t, 2H), 2.88 (t, 2H), 3.99 (t, 2H), 4.03 (t, 2H), 6.80 (d, 2H), 6.90-7.25 (m, 8H), 7.01 (d, 2H), 7.15 (s, 1H), 7.28 (d, 1H), 7.70 (d, 2H) ppm.

Example 441 {3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-methyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide (2.2 mmol) in THF was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crude product was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-alkoxyaniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched using cold water (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated acetophenone was used for further transformation.

To a stirred solution of the 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the residue was treated with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by chromatography (Silica gel). Pure product was obtained by elution with 20-30% EtOAc/hexane (yield ˜70-75%).

To a stirred solution of the N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (1.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of 1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 4.8 mmol) was added, followed by slow addition of acetyl chloride (2 eq., 3.2 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in DCM. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in acetic acid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained by elution with 4-6% MeOH/DCM (yield: 250 mg).

MS m/z 519 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.67 (d, 2H), 7.22 (d, 2H), 7.21 (m, 5H), 6.96 (d, 2H), 6.84 (d, 2H), 4.17 (t, 2H), 4.07 (t, 2H), 3.06 (t, 2H), 2.78 (t, 2H), 2.74 (m, 4H), 2.36 (s, 3H), 2.06 (m, 2H), 1.13 (t, 6H) ppm

Example 442 3-(4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-1-ethyl-piperidine

To a stirred solution of 4-benzyloxyacetophenone (7.0 mmol) in anhydrous DCM (30.0 mL) and MeOH (5.0 mL) at rt, pyridinium bromide perbromide (1.1 eq.) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC. The mixture was diluted with EtOAc (100 ml) and washed with H₂O (2×50 ml), brine (30 ml) and dried with magnesium sulfate. The solvent was then removed in vacuuo to give a white solid. The 1-[4-(benzyloxy)phenyl]-2-bromoethanone was used for further transformation without further purification.

To a stirred solution of 4-(4-fluoro-3-trifluoromethyl-phenoxy)-aniline (1.64 mmol) in anhydrous DMF (30 mL) DIEA (3 eq) was added, followed by slow addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone described above (2 eq), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC and HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in Et₂O. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired alkylated aniline, which was purified by chromatography (Silica gel). Pure product was obtained by elution with 5-20% EtOAc/Hexane (yield ˜50-60%).

To a stirred solution of alkylated aniline described above (1.0 mmol) in anhydrous THF (20 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed by slow addition of valeryl chloride (3 eq, 3.0 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to ambient temperature until completion, as indicated by TLC and HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.0 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained by elution with 5-15% EtOAc/Hexane (yield 80%).

The above product was dissolved in MeOH (20 mL), and Pd/C (100 mg) was added and the heterogeneous mixture was stirred overnight under hydrogen atmosphere using a balloon, according to General Procedure T2. The Pd/C was removed by filtration. The solvent was removed in vacuuo, and the crude 4-(1-{4-[4-fluoro-3-(trifluoromethyl)phenoxy]phenyl}-2-butyl-1H-imidazol-4-yl)phenol was used for further transformation.

A stirred solution of the 4-(1-{4-[4-fluoro-3-(trifluoromethyl)phenoxy]phenyl}-2-butyl-1H-imidazol-4-yl)phenol (1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid sodium hydride (60% dispersion in oil; 1.0 mmol) in portions. The mesylate of 1-(methylamino)piperidin-3-ol was then added to the reaction mixture, which was heated at 90° C. overnight, according to General Procedure T3. After cooling the mix to rt, Et₂O (30 mL) was added to the reaction mixture followed by H₂O (10 mL). The organic layer was washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. The solvent was removed in vacuuo. Pure imidazole was obtained by elution with chromatography in 5-10% MeOH/DCM (yield 52.0 mg).

MS m/z 583 (M+H)⁺:

¹H NMR (CDCl₃): δ 7.7 (m, 2H), 7.3 (m, 3H), 7.24 (m, 2H), 7.13 (s, 1H), 7.07 (d, 2H, J 8.8 Hz), 6.94 (m, 2H), 0.9-4.4 (m, 23H) ppm.

Example 443 diethyl-[3-(4-{1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-2-methyl-1H-imidazol-4-yl}-phenoxy)-propyl]-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of a potassium 4-fluoro-3-trifluoromethyl-phenoxide (2.2 mmol) in THF (may be generated by adding the corresponding alcohol to a 1M solution of potassium t-butoxide in THF) was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the reaction mixture was treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude product could be used directly for further transformation.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion, as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-[4-fluoro-3-(trifluoromethyl)phenoxy]aniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (10 mL) at rt, solid potassium carbonate (8.0 mmol) was added. The mesylate of N,N-diethylaminopropanol (prepared from the corresponding alcohol and methanesulfonyl chloride) (2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was diluted with water and the product was isolated in EtOAc. The combined organic layers were washed with saturated sodium bicarbonate (2×15 ml), water (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated product was purified using silica gel column chromatography. Pure product was obtained with 2-3% MeOH/DCM. (yield 50-60%)

To a stirred solution of the 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (1 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 1.2 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo, the residue was treated with saturated sodium bicarbonate and the product was isolated in EtOAc. The combined organic layers were washed with water (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a stirred solution of the 4-fluoro-3-trifluoromethyl-phenoxy aniline (1.2 eq., 1.2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 3 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (1.0 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of alkylated aniline described above (1.0 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 3.0 mmol) was added, followed by slow addition of acetyl chloride (2 eq., 2.0 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with water and the product was isolated in DCM. The solvent was removed in vacuuo, and the crude amide was purified using silica gel chromatography. Pure product was obtained by elution with 3-4% MeOH/DCM (Yield 40-45%).

To a stirred solution of the amide described above (0.5 mmol) in acetic acid (1 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained by elution with 4-6% MeOH/DCM (yield: 108 mg).

MS m/z 542 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.69 (d, 2H), 7.33 (m, 5H), 7.18 (s, 1H), 7.09 (d, 2H), 6.91 (d, 2H) 4.03 (t, 2H), 2.63 (m, 6H), 2.41 (s, 3H), 2.01 (m, 2H), 1.08 (t, 6H) ppm

Example 444 (3-{4-[4-(4-benzyloxy-phenyl)-2-butyl-imidazol-1-yl]-phenoxy}-propyl)-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide (2.2 mmol) in THF was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crude product was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-(N,N-diethylaminopropoxy)aniline, which was used directly for further transformation without further purification.

To a stirred solution of the 4′-benzyloxyacetophenone (2 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the residue was treated with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (20 mL) and the product was isolated in EtOAc (2×20 mL). The combined organic layers were washed with saturated sodium thiosulfate (2×10 mL), water (2×10 mL) and brine (15 mL). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude alpha-bromoacetophenone was purified by chromatography (Silica gel). Pure product was obtained by elution with 20-30% EtOAc/hexane (yield ˜70-75%).

To a stirred solution of the 4-(N,N-diethylaminopropoxy)aniline (1.2 eq., 2 mmol) in anhydrous DMF (5 mL) the alpha-bromoacetophenone (1.6 mmol) described above was added slowly, according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of alkylated aniline described above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 4.8 mmol) was added, followed by slow addition of valeryl chloride (2 eq., 3.2 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in DCM. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in acetic acid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained by elution with 4-6% MeOH/DCM (yield 179 mg).

MS m/z 512 (M+H)⁺:

¹H NMR (CDCl₃): δ7.69 (d, 2H), 7.15-7.50 (m, 8H), 7.09 (s, 1H), 6.96 (m, 3H), 5.05 (s, 2H), 4.12 (t, 2H), 3.21 (broad m, 2H), 3.15 (q, 4H), 2.64 (t, 2H) 2.38 (broad m, 2H), 1.60 (q, 2H) 1.41 (t, 6H) 1.20-1.35 (m, 2H), 0.81 (t, 6H) ppm.

Example 445 [3-(4-{2-butyl-1-[4-(2,5-difluoro-benzyloxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM (25 mL), TEA (40 mmol, 2 eq) was added and the mixture was cooled to 0° C. To this mixture, methanesulfonyl chloride (30 mmol, 1.5 eq) was added slowly with stirring and the reaction mixture was stirred at 0° C. for an hour and at rt for another hour (until the reaction was complete by HPLC). The solvent was removed and saturated aqueous sodium bicarbonate was added. The product was extracted with EtOAc (3×) and washed with sodium bicarbonate and water. The solvent was removed in vacuuo.

The mesylate from the previous step (20 mmol, 1 eq) was dissolved in anhydrous DMF (25 mL) to which 4-hydroxyacetophenone (20 mmol, 1 eq) and potassium carbonate (60 mmol, 3 eq) were added. The mixture was heated under reflux at 85° C. for 18 h (until the reaction was complete by HPLC), after which it was cooled to rt. Saturated aqueous sodium bicarbonate was added to the mixture, which was then transferred to a separatory funnel. The product was extracted with EtOAc and washed with sodium bicarbonate and water. The solvent was removed in vacuuo and the product 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by flash chromatography (going by increasing gradient up to 10% MeOH in DCM). The overall yield was 60%.

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (6 mL) at 0° C., a 1M solution of a potassium alkoxide (2.2 mmol) in THF (may be generated by adding the 2,5-difluorobenzyl alcohol to a 1M solution of KOBu^(t) in THF) was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. until completion, as indicated by TLC or HPLC. The reaction mixture was then treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crude product could be used directly for further transformation without any purification, or after purifying using silica gel column chromatography.

The nitro intermediate (2 mmol) obtained above was dissolved in MeOH (6 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion, as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford 4-(2,5-difluoro-benzyloxy)aniline, which was used directly for further transformation without further purification (yield 80%).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (6 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to it until completion, as indicated by TLC or HPLC.

The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a solution of 4-(2,5-difluoro-benzyloxy)aniline (1 eq, 2 mmol) in anhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was added, followed by addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (2 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product by elution with 2-4% MeOH/DCM (yield 50%).

To a stirred solution of alkylated aniline described above (1 mmol) in anhydrous DCM (4 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed by a slow addition of valeryl chloride (3 eq, 3 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1 mmol) in acetic acid (4 mL), ammonium acetate (20 mmol, 20 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained by elution with 4-6%

MeOH/DCM (yield 208 mg).

MS m/z 549 (M+H)⁺:

¹H NMR (CDCl₃): δ7.68 (d, 2H), 7.24 (m, 5H), 7.13 (s, 1H), 7.06 (d, 2H), 6.89 (d, 2H), 5.17 (s, 2H), 4.02 (t, 2H), 2.62-2.78 (m, 8H), 1.98 (m, 2H), 1.60 (m, 2H), 1.27 (m, 2H), 1.11 (t, 6H), 0.82 (t, 3H) ppm.

Example 446 3-(S)-(4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxymethyl)-1-ethyl-piperidine

To a stirred solution of 4-benzyloxyacetophenone (7.0 mmol) in anhydrous DCM (30.0 mL) and MeOH (5.0 mL) at rt, pyridinium bromide perbromide (1.1 eq.) was added. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC. The mixture was diluted with EtOAc (100 ml) and washed with H₂O (2×50 ml), brine (30 ml) and dried with magnesium sulfate. The solvent was then removed in vacuuo to give a white solid. The alpha-bromoacetophenone was used for further transformation without further purification.

To a stirred solution of 4-(4-fluoro-3-trifluoromethyl-phenoxy)-aniline (1.64 mmol) in anhydrous DMF (30 mL) DIEA (3 eq) was added, followed by slow addition of the alpha-bromoacetophenone described above (2 eq), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC and HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in Et₂O. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained by elution with 5-20% EtOAc/Hexane (yield ˜50-60%).

To a stirred solution of alkylated aniline described above (1.0 mmol) in anhydrous THF (20 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed by slow addition of valeryl chloride (3 eq, 3.0 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to ambient temperature until completion, as indicated by TLC and HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.0 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained by elution with 5-15% EtOAc/Hexane (yield 80%).

(MS: m/z 562 (M+H)⁺)

The above product was dissolved in MeOH (20 mL), and Pd/C (100 mg) was added and the heterogeneous mixture was stirred overnight under hydrogen atmosphere using a balloon, according to General Procedure T2. The Pd/C was removed by filtration. The solvent was removed in vacuuo, and the crude 4-(1-{4-[4-fluoro-3-(trifluoromethyl)phenoxy]phenyl}-2-butyl-1H-imidazol-4-yl)phenol (MS: m/z 472 (M+H)⁺) was used for further transformation.

A stirred solution of the 4-(1-{4-[4-fluoro-3-(trifluoromethyl)phenoxy]phenyl}-2-butyl-1H-imidazol-4-yl)phenol (1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid sodium hydride (60% dispersion in oil; 1.0 mmol) in portions. The mesylate of [(3S)-1-ethylpiperidin-3-yl]methanol (1.5-2.0 eq) was added to the reaction mixture, which was heated at 90° C. overnight, according to General Procedure T3. After cooling the mix to rt, Et₂O (30 mL) was added to the reaction mixture followed by H₂O (10 mL). The organic layer was washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. The solvent was removed in vacuuo. Pure imidazole was obtained by elution with chromatography in 5-10% MeOH/DCM (yield 50.0 mg).

MS m/z 597 (M+H)⁺:

¹H NMR (CDCl₃): δ 7.70 (d, 2H), 7.20-7.35 (m, 5H), 7.14 (s, 1H), 7.08 (d, 2H), 6.92 (d, 2H), 4.05 (m, 1H), 3.92 (m, 2H), 2.60 (m, 4H), 1.0-2.5 (m, 18H) ppm.

Example 447 (3-{4-[4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-(2,4,4-trimethyl-pentyl)-imidazol-1-yl]-phenoxy}-propyl)-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide (2.2 mmol) in THF was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crude product was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-alkoxyaniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched using cold water (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated acetophenone was used for further transformation.

To a stirred solution of the 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the residue was treated with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by chromatography (Silica gel). Pure product was obtained by elution with 20-30% EtOAc/hexane (yield ˜70-75%).

To a stirred solution of the N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (1.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of 1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 4.8 mmol) was added, followed by slow addition of 3,5,5-trimethyl hexanoyl chloride (2 eq., 3.2 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in DCM. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in acetic acid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained by elution with 4-6% MeOH/DCM (yield: 296 mg).

MS m/z value (M+H)⁺: 617

¹H NMR (400 MHz, CDCl₃): δ7.69 (d, 2H), 7.22 (d, 2H), 7.21 (m, 5H), 6.96 (d, 2H), 6.88 (d, 2H), 4.18 (t, 2H), 4.07 (t, 2H), 3.09 (t, 2H), 2.88 (d, 2H), 2.79 (m, 6H), 2.05 (m, 3H), 1.11 (t, 6H), 0.97 (d, 2H), 0.87 (d, 3H), 0.78 (s, 9H) ppm

Example 448 3-(R)-(4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxymethyl)-1-ethyl-piperidine

To a stirred solution of 4-benzyloxyacetophenone (7.0 mmol) in anhydrous DCM (30.0 mL) and MeOH (5.0 mL) at rt, pyridinium bromide perbromide (1.1 eq.) was added. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC. The mixture was diluted with EtOAc (100 ml) and washed with H₂O (2×50 ml), brine (30 ml) and dried with magnesium sulfate. The solvent was then removed in vacuuo to give a white solid. The alpha-bromoacetophenone was used for further transformation without further purification.

To a stirred solution of 4-(4-fluoro-3-trifluoromethyl-phenoxy)-aniline (1.64 mmol) in anhydrous DMF (30 mL) DIEA (3 eq) was added, followed by slow addition of the alpha-bromoacetophenone described above (2 eq), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC and HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in Et₂O. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained by elution with 5-20% EtOAc/Hexane (yield ˜50-60%).

To a stirred solution of alkylated aniline described above (1.0 mmol) in anhydrous THF (20 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed by slow addition of valeryl chloride (3 eq, 3.0 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to ambient temperature until completion, as indicated by TLC and HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.0 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained by elution with 5-15% EtOAc/Hexane (yield 80%). (MS: m/z 562 (M+H)⁺)

The above product was dissolved in MeOH (20 mL), and Pd/C (100 mg) was added and the heterogeneous mixture was stirred overnight under hydrogen atmosphere using a balloon, according to General Procedure T2. The Pd/C was removed by filtration. The solvent was removed in vacuuo, and the crude 4-(1-{4-[4-fluoro-3-(trifluoromethyl)phenoxy]phenyl}-2-butyl-1H-imidazol-4-yl)phenol (MS: m/z 472 (M+H)⁺) was used for further transformation.

A stirred solution of the 4-(1-{4-[4-fluoro-3-(trifluoromethyl)phenoxy]phenyl}-2-butyl-1H-imidazol-4-yl)phenol (1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid sodium hydride (60% dispersion in oil; 1.0 mmol) in portions. The mesylate of [(3R)-1-ethylpiperidin-3-yl]methanol (1.5-2.0 eq) was added to the reaction mixture, which was heated at 90° C. overnight, according to General Procedure T3. After cooling the mix to rt, Et₂O (30 mL) was added to the reaction mixture followed by H₂O (10 mL). The organic layer was washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. The solvent was removed in vacuuo. Pure imidazole was obtained by elution with chromatography in 5-10% MeOH/DCM (yield 50.0 mg).

MS m/z 597 (M+H)⁺:

¹H NMR (CDCl₃): δ 7.70 (d, 2H), 7.20-7.35 (m, 5H), 7.14 (s, 1H), 7.08 (d, 2H,), 6.92 (d, 2H), 4.05 (m, 1H), 3.92 (m, 2H), 2.60 (m, 4H), 1.0-2.5 (m, 18H). ppm.

Example 449 [3-(4-{2-butyl-1-[4-(3-tert-butyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM (25 mL), TEA (40 mmol, 2 eq) was added and the mixture was cooled to 0° C. To this mixture, methanesulfonyl chloride (30 mmol, 1.5 eq) was added slowly with stirring and the reaction mixture was stirred at 0° C. for an hour and at rt for another hour (until the reaction was complete by HPLC). The solvent was removed and saturated aqueous sodium bicarbonate was added. The product was extracted with EtOAc (3×) and washed with sodium bicarbonate and water. The solvent was removed in vacuuo.

The mesylate from the previous step (20 mmol, 1 eq) was dissolved in anhydrous DMF (25 mL) to which 4-hydroxyacetophenone (20 mmol, 1 eq) and potassium carbonate (60 mmol, 3 eq) were added. The mixture was heated under reflux at 85° C. for 18 h (until the reaction was complete by HPLC), after which it was cooled to rt. Saturated aqueous sodium bicarbonate was added to the mixture, which was then transferred to a separatory funnel. The product was extracted with EtOAc and washed with sodium bicarbonate and water. The solvent was removed in vacuuo and the product 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by flash chromatography (going by increasing gradient up to 10% MeOH in DCM). The overall yield was 60%.

4-Methoxyphenol (10 mmol) was dissolved in 15 ml of anhydrous DMF and potassium carbonate (30 mmol) was added with stirring at rt. 4-Fluoronitrobenzene (10 mmol) was added to this mixture, which was then heated under reflux at 80° C. for 18 h. The reaction was quenched with 30 ml of water and 30 ml of sodium bicarbonate, extracted with EtOAc (3×50 ml) and washed with sodium bicarbonate and water. The EtOAc layer was dried over anhydrous sodium sulfate and filtered, after which the solvent was removed in vacuuo.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOH (30 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-(3-tert-butyl-phenoxy)aniline, which was used directly for further transformation without further purification (yield 80%).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (6 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a solution of 4-(3-tert-butyl-phenoxy)aniline (1 eq, 2 mmol) in anhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was added, followed by addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (2 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product by elution with 2-4% MeOH/DCM (yield 51%).

To a stirred solution of alkylated aniline described above (1 mmol) in anhydrous DCM (4 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed by a slow addition of valeryl chloride (3 eq, 3 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1 mmol) in acetic acid (4 mL), ammonium acetate (20 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained by elution with 4-6% MeOH/DCM (yield 177 mg).

MS m/z 555 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ 7.7 (d, 2H), 7.3 (m, 4H), 7.1-7.2 (m, 5H), 6.9 (d, 2H), 4.0 (t, 2H), 2.8-3.0 (m, 8H), 2.0 (m, 2H), 1.6 (m, 2H), 1.4 (m, 2H), 1.2 (15H), 0.8 (t, 3H) ppm

Example 450 {3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-methoxymethyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide (2.2 mmol) in THF was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crude product was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-alkoxyaniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched using cold water (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated acetophenone was used for further transformation.

To a stirred solution of the 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the residue was treated with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by chromatography (Silica gel). Pure product was obtained by elution with 20-30% EtOAc/hexane (yield ˜70-75%).

To a stirred solution of the N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (1.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of 1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 4.8 mmol) was added, followed by slow addition of methoxy acetyl chloride (2 eq., 3.2 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in DCM. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in acetic acid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained by elution with 4-6% MeOH/DCM (yield: 265 mg).

MS m/z 549 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.72 (d, 2H), 7.37 (d, 2H), 7.48 (m, 5H), 6.98 (d, 2H), 6.85 (d, 2H), 4.41 (s, 2H), 4.18 (t, 2H), 4.07 (t, 2H), 3.45 (s, 3H), 3.06 (t, 2H), 2.86 (m, 6H), 2.08 (m, 2H), 1.17 (t, 6H) ppm

Example 451 (3-{4-[4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-(1-ethyl-propyl)-imidazol-1-yl]-phenoxy}-propyl)-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide (2.2 mmol) in THF was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crude product was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-alkoxyaniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched using cold water (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated acetophenone was used for further transformation.

To a stirred solution of the 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the residue was treated with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by chromatography (Silica gel). Pure product was obtained by elution with 20-30% EtOAc/hexane (yield ˜70-75%).

To a stirred solution of the N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (1.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of 1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 4.8 mmol) was added, followed by slow addition of 2-ethyl butyryl chloride (2 eq., 3.2 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in DCM. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in acetic acid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained by elution with 4-6% MeOH/DCM (yield: 230 mg).

MS m/z 575 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.71 (d, 2H), 7.27 (m, 6H), 7.06 (s, 1H), 6.95 (d, 2H), 6.87 (d, 2H), 4.09 (t, 2H), 4.02 (t, 2H), 3.07 (t, 2H), 2.72 (m, 6H), 2.49 (m, 1H), 2.06 (m, 2H), 1.82 (m, 2H), 1.68 (m, 2H), 1.08 (t, 6H), 0.96 (t, 3H), 0.88 (t, 3H) ppm

Example 452 (3-{4-[4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-(3-phenoxy-propyl)-imidazol-1-yl]-phenoxy}-propyl)-diethyl-amine

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-alkoxyaniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched using cold water (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated acetophenone was used for further transformation.

To a stirred solution of the 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to it until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the residue was treated with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by chromatography (Silica gel). Pure product was obtained by elution with 20-30% EtOAc/hexane (yield ˜70-75%).

To a stirred solution of the N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (1.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of 1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 4.8 mmol) was added, followed by slow addition of 4-phenoxy butyryl chloride (2 eq., 3.2 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in DCM. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in acetic acid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained by elution with 4-6% MeOH/DCM (yield: 250 mg).

MS m/z 638 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.69 (d, 2H), 7.23-7.25 (m, 8H), 7.12 (s, 1H), 6.92 (m 5H), 6.81 (d, 2H), 4.18 (t, 2H), 4.09 (t, 2H), 3.95 (t, 2H), 3.07 (t, 2H), 2.85 (m, 8H), 2.22 (m, 2H), 2.05 (m, 2H), 1.20 (t, 6H) ppm

Example 453 (3-{4-[4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-(1-propyl-butyl)-imidazol-1-yl]-phenoxy}-propyl)-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide (2.2 mmol) in THF was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crude product was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-alkoxyaniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched using cold water (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated acetophenone was used for further transformation.

To a stirred solution of the 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to it until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the residue was treated with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by chromatography (Silica gel). Pure product was obtained by elution with 20-30% EtOAc/hexane (yield ˜70-75%).

To a stirred solution of the N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (1.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of 1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 4.8 mmol) was added, followed by slow addition of 2-N-propyl-N-valeryl chloride (2 eq., 3.2 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in DCM. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in acetic acid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained by elution with 4-6% MeOH/DCM (yield: 288 mg).

MS m/z 602 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.69 (d, 2H), 7.23-7.25 (m, 6H), 7.04 (s, 1H), 6.97 (d, 2H), 6.87 (d, 2H), 4.18 (t, 2H), 4.09 (t, 2H), 3.06 (t, 2H), 2.87 (m, 6H), 2.63 (m, 1H), 2.13 (m, 2H), 1.81 (m, 2H), 1.54 (m, 2H), 1.17 (t, 10H), 0.89 (t, 6H) ppm

Example 454 {3-[4-(2-(4-chloro-phenoxymethyl)-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide (2.2 mmol) in THF was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crude product was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-alkoxyaniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched using cold water (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated acetophenone was used for further transformation.

To a stirred solution of the 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the residue was treated with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by chromatography (Silica gel). Pure product was obtained by elution with 20-30% EtOAc/hexane (yield ˜70-75%).

To a stirred solution of the N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (1.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of 1-{4-[(2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 4.8 mmol) was added, followed by slow addition of 4-chlorophenoxy acetyl chloride (2 eq., 3.2 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in DCM. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in acetic acid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to it and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained by elution with 4-6% MeOH/DCM (yield: 250 mg).

MS m/z 644 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.72 (d, 2H), 7.36 (d, 2H), 7.23-7.25 (m, 4H), 7.23 (m, 4H), 6.91 (m, 5H), 4.95 (s, 2H), 4.17 (t, 2H), 4.05 (t, 2H), 3.07 (m, 8H), 2.21 (m, 2H), 1.27 (t, 6H) ppm

Example 455 {3-[4-(2-benzyloxymethyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide (2.2 mmol) in THF was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. for 1 h and allowed to warm to it until completion, as indicated by TLC or HPLC. The reaction mixture was then treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crude product was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-alkoxyaniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched using cold water (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated acetophenone was used for further transformation.

To a stirred solution of the 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the residue was treated with saturated sodium, bicarbonate. The aqueous layer was poured into EtOAc (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by chromatography (Silica gel). Pure product was obtained by elution with 20-30% EtOAc/hexane (yield ˜70-75%).

To a stirred solution of the N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (1.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of 1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 4.8 mmol) was added, followed by slow addition of benzyloxyacetyl chloride (2 eq., 3.2 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in DCM. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in acetic acid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained by elution with 4-6% MeOH/DCM (yield: 350 mg).

MS m/z 624 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.71 (d, 2H), 7.68 (d, 2H), 7.31 (m, 7H), 7.25 (d, 2H), 7.21 (s, 1H), 6.94 (d, 2H), 6.89 (d, 2H), 4.58 (s, 2H), 4.49 (s, 2H), 4.15 (t, 2H), 4.08 (t, 2H), 3.11 (t, 2H), 2.89 (m, 6H), 2.18 (m, 2H), 1.35 (t, 6H) ppm

Example 456 {3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-isobutyl-5-methyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 1-{4-[2-(4-chloro-phenyl)-ethoxy]phenyl}-propan-1-one (1.0 mmol) in dioxane (10.0 mL) at rt, pyridinium bromide perbromide (1.1 eq) was added. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC. The mixture was diluted with EtOAc (100 ml) and washed with H₂O (2×50 ml), brine (30 ml) and dried with magnesium sulfate, The solvent was then removed in vacuuo to give a white solid. The alpha-bromoketone was used for further transformation without further purification.

A solution of the above alpha-bromoketone (1.0 eq), N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq), and DIEA (1.5 eq) in anhydrous DMF (10 mL) was stirred under nitrogen at rt until completion, as indicated by HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in Et₂O. The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was removed in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained by elution with 2-7% MeOH/DCM (yield ˜55%).

To a stirred solution of alkylated aniline described above (0.55 mmol) in anhydrous THF (5 mL) at 0° C., TEA (3.0 mmol) was added, followed by slow addition of isovaleryl chloride (5.0 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to ambient temperature until completion, as indicated by HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (0.55 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole (yield 190 mg).

MS m/z 574 (M+H)⁺:

Example 457 {3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-isobutyl-5-propyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 1-{4-[2-(4-chloro-phenyl)-ethoxy]phenyl}-pentan-1-one (1.0 mmol) in dioxane (10.0 mL) at rt, pyridinium bromide perbromide (1.1 eq.) was added. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC. The mixture was diluted with EtOAc (100 ml) and washed with H₂O (2×50 ml), brine (30 ml) and dried with magnesium sulfate. The solvent was then removed in vacuuo to give a white solid. The alpha-bromophenone was used for further transformation.

A solution of the above alpha-bromophenone (1.0 eq), N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq), and DIEA (1.5 eq) in anhydrous DMF (10 mL) was stirred under nitrogen at rt until completion, as indicated by HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in Et₂O. The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was removed in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained by elution with 2-5% MeOH/DCM (yield ˜50%).

To a stirred solution of alkylated aniline described above (0.48 mmol) in anhydrous THF (5 mL) at 0° C., DMAP (0.25 eq) was added, followed by slow addition of isovaleryl chloride (5.0 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to ambient temperature until completion, as indicated by HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (0.48 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole (yield 180 mg). MS m/z 602 (M+H)⁺:

¹H NMR (CDCl₃): δ7.58 (d, 2H), 7.28 (d, 2H), 7.21 (d, 2H), 7.11 (d, 2H), 6.98 (d, 2H), 6.91 (d, 2H), 4.17 (t, 2H), 4.08 (t, 2H), 3.07 (t, 2H), 2.6 (t, 2H), 2.57 (q, 6H), 2.47 (t, 4H), 2.36 (d, 2H), 2.0 (m, 3H), 1.3 (m, 2H), 1.05 (t, 6H), 0.82 (d, 6H), 0.72 (t, 3, H) ppm.

Example 458 {3-[4-(5-butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-isobutyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of 1-{4-[2-(4-chloro-phenyl)-ethoxy]phenyl}-hexan-1-one (0.785 mmol) in dioxane (10.0 mL) at rt, pyridinium bromide perbromide (1.1 eq) was added. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC. The mixture was diluted with EtOAc (100 ml) and washed with H₂O (2×50 ml), brine (30 ml) and dried with magnesium sulfate. The solvent was then removed in vacuuo to give a white solid. The alpha-bromophenone was used for further transformation.

A solution of the above alpha-bromophenone (1.0 eq), N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq), and DIEA (1.5 eq) in anhydrous DMF (10 mL) was stirred under nitrogen at rt for 24 hour. The reaction mixture was then diluted with cold H₂O and the product was isolated in Et₂O. The combined organic layers Were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained by elution with 2-7% MeOH/DCM (yield ˜47%).

To a stirred solution of alkylated aniline described above (0.31 mmol) in anhydrous THF (5 mL) at 0° C., DMAP (0.25 eq) was added, followed by slow addition of isovaleryl chloride (5.0 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to ambient temperature until completion, as indicated by HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (0.31 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole (yield 108 mg).

MS m/z 616 (M+H)⁺:

¹H NMR (CDCl₃): δ7.6 (d, 2H), 7.28 (d, 2H), 7.21 (d, 2H), 7.11 (d, 2H), 7.00 (d, 2H), 6.90 (d, 2H), 4.18 (t, 2H), 4.08 (t, 2H, 3.06 (t, 2H), 2.45-2.65 (m, 8H), 2.36 (d, 2H), 2.0 (m, 4H), 0.7-1.3 (m, 18H) ppm.

Example 459 {4-{4-{2-(4-chloro-phenyl)-ethoxy]-phenyl}-1-[4-(3-diethylamino-propoxy)-phenyl]-1H-imidazol-2-yl}-MeOH

To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of a potassium diethylaminopropoxide (2.2 mmol) in THF was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crude product was used directly for further transformation.

The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-alkoxyaniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched using cold water (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), water (2×10 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated acetophenone was used for further transformation.

To a stirred solution of the 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the residue was treated with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (20 ml) and the product was isolated in EtOAc (2×20 ml). The combined organic layers were washed with saturated sodium bicarbonate (2×10 ml), and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by chromatography (Silica gel). Pure product was obtained by elution with 20-30% EtOAc/hexane (yield ˜70-75%).

To a stirred solution of the N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (1.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of 1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-phenylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 4.8 mmol) was added, followed by slow addition of benzyloxyacetyl chloride (2 eq., 3.2 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in DCM. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1.6 mmol) in acetic acid (4 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained by elution with 4-6% MeOH/DCM (yield 30-40%).

To a stirred solution of the pure imidazole (0.48 mmol) described above 6N HCl was added and the reaction mixture was refluxed overnight. The reaction mixture was then cooled to rt and neutralized with 3N sodium hydroxide solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained by elution with 4-6% MeOH/DCM (yield: 130 mg).

MS m/z 534 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.66 (d, 2H), 7.41 (d, 2H), 7.28 (d, 2H), 7.22 (m, 3H), 6.99 (d, 2H), 6.89 (d, 2H), 4.62 (s, 2H), 4.17 (t, 2H), 4.08 (t, 2H), 3.07 (t, 2H), 2.88 (m, 6H), 2.18 (m, 2H), 1.24 (t, 6H) ppm

Example 460 diethyl-[3-(4-{2-isobutyl-4-[4-(4-phenoxy-benzyloxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-amine

To a stirred solution of N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq., 2.5 mmol) in anhydrous DMF (20 mL) DIEA (3 eq) was added, followed by slow addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone (2.5 mmol). The reaction mixture was stirred under nitrogen at rt until completion, as indicated by HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in Et₂O. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained by elution with 2-7% MeOH/DCM (yield ˜30%).

To a stirred solution of the alkylated aniline described above (0.88 mmol) in anhydrous DCM (10 mL) at 0° C., TEA (3.0 mmol) was added, followed by slow addition of isovaleryl chloride (5.0 eq), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to ambient temperature until completion, as indicated by HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (0.88 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the cyclized product, (crude ˜80%) which was taken to the next transformation without purification.

The above product was dissolved in MeOH (20 mL), Pd/C (100 mg) was added and the heterogeneous mixture was stirred overnight under H₂ atmosphere using a balloon, according to General Procedure T2. The Pd/C was removed by filtration. The solvent was removed in vacuuo, and the crude 4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenol was used for further transformation without purification.

A stirred solution of the 4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenol (1.0 eq) obtained above in anhydrous DMF (5.0 mL) was treated with solid sodium hydride (60% dispersion in oil; 1.0 mmol) in portions. The mesylate of (4-phenoxyphenyl)methanol (1.1 eq) was added to the reaction mixture, which was stirred at rt overnight, according to General Procedure T3. Et₂O (30 mL) was added to the reaction mixture followed by H₂O (10 mL). The organic layer was washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. The solvent was removed in vacuuo. Pure imidazole was obtained by elution with chromatography in 5-10% MeOH/DCM (yield 70.0 mg).

MS m/z 604 (M+H)⁺:

¹H NMR (CDCl₃): δ 7.70 (d, 2H) 6.9-7.4 (m, 16H), 5.0 (s, 2H), 4.1 (t, 2H), 3.0 (m, 6H), 2.52 (d), 2.26 (m, 2H), 2.01 (m, 1H), 1.31 (t, 6H), 0.84 (d, 6H) ppm.

Example 461 [3-(4-{4-[4-(4-benzyloxy-benzyloxy)-phenyl]-2-isobutyl-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq., 2.5 mmol) in anhydrous DMF (20 mL) DIEA (3 eq) was added, followed by slow addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone (2.5 mmol). The reaction mixture was stirred under nitrogen at rt until completion, as indicated by HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in Et₂O. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained by elution with 2-7% MeOH/DCM (yield ˜30%).

To a stirred solution of the alkylated aniline described above (0.88 mmol) in anhydrous DCM (10 mL) at 0° C., TEA (3.0 mmol) was added, followed by slow addition of isovaleryl chloride (5.0 eq), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to ambient temperature until completion, as indicated by HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (0.88 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the cyclized product, (crude ˜80%) which was taken to the next transformation without purification.

The above product was dissolved in MeOH (20 mL), Pd/C (100 mg) was added and the heterogeneous mixture was stirred overnight under H₂ atmosphere using a balloon, according to General Procedure T2. The Pd/C was removed by filtration. The solvent was removed in vacuuo, and the crude 4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenol was used for further transformation without purification.

A stirred solution of 4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenol (1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid sodium hydride (60% dispersion in oil; 1.0 mmol) in portions. The mesylate of [4-(benzyloxy)phenyl]methanol (1.1 eq) was added to the reaction mixture, and stirred at rt overnight, according to General Procedure T3. Et₂O (30 mL) was added to the reaction mixture followed by H₂O (10 mL). The organic layer was washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. The solvent was removed in vacuuo. Pure imidazole was obtained from chromatography with 5-10% MeOH/DCM (yield 70.0 mg).

MS m/z 618 (M+H)⁺:

¹H NMR (CDCl₃): δ7.70 (d, 2H), 7.3-7.45 (m, 7H), 7.21 (d, 2H), 7.1 (s, 1H), 6.9 (m, 6H), 5.07 (s, 2H), 5.00 (s, 2H), 4.1 (t, 2H), 3.0 (m, 6H), 2.52 (d, 2H), 2.26 (m, 2H), 2.01 (m, 1H), 1.31 (t, 6H), 0.84 (d, 6H) ppm.

Example 462 [3-(4-{4-[4-(2-benzenesulfonylmethyl-benzyloxy)-phenyl]-2-isobutyl-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq., 2.5 mmol) in anhydrous DMF (20 mL) DIEA (3 eq) was added, followed by slow addition of 1-[4-(benzyloxy)phenyl]-2-bromoethanone (2.5 mmol). The reaction mixture was stirred under nitrogen at rt until completion, as indicated by HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in Et₂O. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained by elution with 2-7% MeOH/DCM (yield ˜30%).

To a stirred solution of the alkylated aniline described above (0.88 mmol) in anhydrous DCM (10 mL) at 0° C., TEA (3.0 mmol) was added, followed by slow addition of isovaleryl chloride (5.0 eq), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to ambient temperature until completion, as indicated by HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (0.88 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the cyclized product, (crude ˜80%) which was taken to the next transformation without purification.

The above product was dissolved in MeOH (20 mL), Pd/C (100 mg) was added and the heterogeneous mixture was stirred overnight under H₂ atmosphere using a balloon, according to General Procedure T2. The Pd/C was removed by filtration. The solvent was removed in vacuuo, and the crude 4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenol was used for further transformation without purification.

A stirred solution of 4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenol (1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid sodium hydride (60% dispersion in oil; 1.0 mmol) in portions. The mesylate of {2-[(phenylsulfonyl)methyl]phenyl}methanol (1.1 eq) was added to the reaction mixture, and stirred at rt overnight, according to General Procedure T3. Et₂O (30 mL) was added to the reaction mixture followed by H₂O (10 mL). The organic layer was washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. The solvent was removed in vacuuo. Pure imidazole was obtained from chromatography with 5-10% MeOH/DCM (yield 77 mg).

MS m/z 666 (M+H)⁺:

¹H NMR (CDCl₃): δ7.6-7.73 (m, 6), 7.3-7.5 (m, 4H), 7.20 (d, 2H), 7.1 (m, 2H), 6.97 (d, 2H), 6.9 (d, 2H), 4.93 (s, 2H), 4.5 (s, 2H), 4.07 (t, 2H), 2.6 (t, 2H), 2.63 (q, 4H), 2.53 (d, 2H), 2.01 (m, 3H), 1.08 (t, 6H), 0.85 (d, 6H) ppm.

Example 463 diethyl-[3-(4-{2-isobutyl-4-[4-(3,4,5-trimethoxy-benzyloxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-amine

To a stirred solution of N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq., 2.5 mmol) in anhydrous DMF (20 mL) DIEA (3 eq) was added, followed by slow addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone (2.5 mmol). The reaction mixture was stirred under nitrogen at rt until completion, as indicated by HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in Et₂O. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained from 2-7% MeOH/DCM (yield ˜30%).

To a stirred solution of the alkylated aniline described above (0.88 mmol) in anhydrous DCM (10 mL) at 0° C., TEA (3.0 mmol) was added, followed by slow addition of isovaleryl chloride (5.0 eq), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to ambient temperature until completion, as indicated by HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (0.88 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4.

The reaction mixture was stirred at 100° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the cyclized product, (crude ˜80%) which was taken to the next transformation without purification.

The above product was dissolved in MeOH (20 mL), Pd/C (100 mg) was added and the heterogeneous mixture was stirred overnight under H₂ atmosphere using a balloon, according to General Procedure T2. The Pd/C was removed by filtration. The solvent was removed in vacuuo, and the crude 4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenol was used for further transformation without purification.

A stirred solution of 4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenol (1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid sodium hydride (60% dispersion in oil; 1.0 mmol) in portions. The mesylate of (3,4,5-trimethoxyphenyl)methanol (1.1 eq) was added to the reaction mixture, and stirred at rt overnight, according to General Procedure T3. Et₂O (30 mL) was added to the reaction mixture followed by H₂O (10 mL). The organic layer was washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. The solvent was removed in vacuuo. Pure imidazole was obtained from chromatography with 5-10% MeOH/DCM (yield 66 mg).

MS m/z 602 (M+H)⁺:

¹H NMR (CDCl₃): δ7.71 (d, 2H), 7.21 (d, 2H), 6.97 (m, 4H), 6.66 (s, 1H), 5 (s, 2H), 4.1 (t, 2H), 3.86 (s, 6H), 3.82 (s, 3H), 3.0 (m, 6H), 2.51 (d, 2H), 2.25 (m, 2H), 2.01 (m, 1H), 1.3 (t, 6H), 0.84 (d, 6H) ppm.

Example 464 [3-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added. The mesylate prepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched by treating the mixture with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated product was used for further transformation after purifying using silica gel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (5.2 mmol) in anhydrous MeOH (10 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 6.2 mmol) was added slowly in small portions, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a stirred solution of 4-amino-4′-chlorodiphenyl ether (1.2 eq., 6.2 mmol) in anhydrous DMF (10 mL) DIEA (3 eq. 16 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (5.2 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H₂O and the product was extracted in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product obtained from 2-4% MeOH/DCM (yield ˜22%).

To a stirred solution of alkylated 4-amino-4′-chlorodiphenyl ether described above (0.4 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 1.2 mmol) was added, followed by slow addition of isovaleryl chloride (3 eq., 1.2 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the 2-[4-(4-chlorophenoxy)-phenylamino]-1-[4-(3-diethylamino-propoxy)-phenyl]-ethanone (0.4 mmol) obtained as above in acetic acid (3 mL), solid ammonium acetate (8 mmol) was added in one portion, according to General Procedure R4. The reaction mixture was then heated to 100° C. overnight. The reaction mixture was cooled to rt, and treated with saturated aqueous sodium bicarbonate solution while stirring to until the pH was 7-8. The contents were extracted with EtOAc (2×15 mL). The combined organic layers was washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired N-aryl imidazole. The crude product was purified using silica gel column chromatography (2-5% MeOH/DCM) (yield 117 mg).

MS m/z 532 (M+H)⁺:

¹H NMR (CDCl₃): δ7.63 (d, 2H), 7.28 (d, 2H), 7.21 (d, 2H), 7.06 (s, 1H), 7.01 (d, 2H), 6.98 (d, 2H), 6.83 (d, 2H), 3.99 (t, 2H), 2.79 (t, 2H), 2.72 (q, 4H), 2.49 (d, 2H), 2.30-1.90 (m, 3H), 1.10 (t, 6H), 0.80 (d, 6H) ppm.

Example 465 [3-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-(2-cyclopentyl-ethyl)-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added. The mesylate prepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched by treating the mixture with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated product was used for further transformation after purifying using silica gel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (5.2 mmol) in anhydrous MeOH (10 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 6.2) was added slowly in small portions, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a stirred solution of 4-amino-4′-chlorodiphenyl ether (1.2 eq., 6.2 mmol) in anhydrous DMF (10 mL) DIEA (3 eq. 16 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (5.2 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H₂O and the product was extracted in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product obtained from 2-4% MeOH/DCM (yield ˜22%).

To a stirred solution of alkylated 4-amino-4′-chlorodiphenyl ether described above (0.4 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 1.2 mmol) was added, followed by slow addition of 3-cyclopentylpropionyl chloride (3 eq., 1.2 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the 2-[4-(4-chlorophenoxy)-phenylamino]-1-[4-(3-diethylamino-propoxy)-phenyl]-ethanone (0.4 mmol) obtained as above in acetic acid (3 mL), solid ammonium acetate (8 mmol) was added in one portion, according to General Procedure R4. The reaction mixture was then heated to 100° C. overnight. The reaction mixture was cooled to rt, and treated with saturated aqueous sodium bicarbonate solution while stirring to until the pH was 7-8. The contents were extracted with EtOAc (2×15 mL). The combined organic layers was washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired N-aryl imidazole. The crude product was purified using silica gel column chromatography (2-5% MeOH/DCM) (yield 180 mg).

MS m/z 572 (M+H)⁺:

¹H NMR (CDCl₃): δ7.69 (d, 2H), 7.35 (d, 2H), 7.29 (d, 2H), 7.14 (s, 1H), 7.08 (d, 2H), 7.02 (d, 2H), 6.89 (d, 2H), 4.05 (t, 2H), 2.95 (t, 2H) 2.85 (q, 4H), 2.71-2.65 (m, 2H), 2.19-2.12 (m, 3H), 1.72-1.61 (m, 4H), 1.59-1.42 (m, 4H), 1.21 (t, 6H), 1.01 (m, 2H) ppm.

Example 466 [3-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-phenethyl-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added. The mesylate prepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched by treating the mixture with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated product was used for further transformation after purifying using silica gel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (5.2 mmol) in anhydrous MeOH (10 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 6.2) was added slowly in small portions, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a stirred solution of 4-amino-4′-chlorodiphenyl ether (1.2 eq., 6.2 mmol) in anhydrous DMF (10 mL) DIEA (3 eq. 16 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (5.2 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H₂O and the product was extracted in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product obtained from 2-4% MeOH/DCM (yield -22%).

To a stirred solution of the alkylated 4-chloroalkoxy aniline described above (0.4 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 1.2 mmol) was added, followed by slow addition of hydrocinnamoyl chloride (3 eq., 1.2 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the 2-[4-(4-chlorophenoxy)-phenylamino]-1-[4-(3-diethylamino-propoxy)-phenyl]-ethanone (˜0.4 mmol) obtained as above in acetic acid (3 mL), solid ammonium acetate (8 mmol) was added in one portion, according to General Procedure R4. The reaction mixture was then heated to 100° C. overnight. The reaction mixture was cooled to rt, and treated with saturated aqueous sodium bicarbonate solution while stirring to until the pH was 7-8. The contents were extracted with EtOAc (2×15 mL). The combined organic layers was washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired N-aryl imidazole. The crude product was purified using silica gel column chromatography (2-4% MeOH/DCM) (yield 50 mg).

MS m/z 580 (M+H)⁺:

¹H NMR (CDCl₃): δ8.41 (m, 2H), 7.92 (m, 2H), 7.62 (d, 2H, 7.33 (d, 2H), 7.25-7.21 (m, 2H), 7.13-7.08 (m, 1H), 7.04 (s, 1H), 6.98 (m, 2H), 6.92 (m, 2H), 6.75 (m, 2H), 4.05 (t, 2H), 3.31 (m, 2H), 3.26-3.05 (m, 6H), 2.35 (m, 2H), 1.40 (t, 6H), 1.21 (m, 2H) ppm.

Example 467 [3-(4-{2-(4-tert-butyl-phenoxymethyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM (25 mL), TEA (40 mmol, 2 eq) was added and the mixture was cooled to 0° C. To this mixture, methanesulfonyl chloride (30 mmol, 1.5 eq) was added slowly with stirring and the reaction mixture was stirred at 0° C. for an hour and at rt for another hour (until the reaction was complete by HPLC). The solvent was removed and to this saturated aqueous sodium bicarbonate was added. The product was extracted with EtOAc (3×) and washed with sodium bicarbonate and water. The solvent was removed in vacuuo.

The mesylate from the previous step (20 mmol, 1 eq) was dissolved in anhydrous DMF (25 mL) to which 4-hydroxyacetophenone (20 mmol, 1 eq) and potassium carbonate (60 mmol, 3 eq) were added. The mixture was heated under reflux at 85° C. for 18 h (until the reaction was complete by HPLC), after which it was cooled to rt. Saturated aqueous sodium bicarbonate was added to the mixture, which was then transferred to a separatory funnel. The product was extracted with EtOAc and washed with sodium bicarbonate and water. The solvent was removed in vacuuo and the product 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by flash chromatography (going by increasing gradient up to 10% MeOH in DCM). The overall yield was 60%.

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (5 mmol) in anhydrous MeOH (10 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a solution of 4-chlorophenoxy aniline (1 eq, 5 mmol) in anhydrous DMF (10 mL), DIEA (3 eq 15 mmol) was added, followed by addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (5 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product obtained from 2-4% MeOH/DCM (yield 52%).

To a solution of 2-[4-(4-chlorophenoxy)-phenylamino]-1-[4-(3-diethylamino-propoxy)-phenyl]-ethanone described above (2 mmol) in anhydrous DCM (5 mL), PS-carbodimide (2 eq, 4 mmol) and 4-t-butylphenoxy-acetic acid (3 mmol) were added. The reaction mixture was shaken overnight and next day filtered to give the desired amide. The crude amide was used for further transformation.

To a stirred solution of the amide described above (2 mmol) in acetic acid (8 mL), ammonium acetate (20 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield 255 mg).

MS m/z 638 (M+H)⁺:

¹H NMR (CDCl₃): δ7.72 (d, 2H), 7.44 (d, 2H), 7.28-7.35 (m, 5H), 6.8-7.1 (m, 8H), 5.01 (s, 2H), 4.06 (t, 2H), 3.13-3.24 (m, 6H), 2.28 (m, 2H), 1.23-1.38 (m, 15H) ppm.

Example 468 [3-(4-{2-butyl-1-[4-(2,4-dichloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 2,4-dichlorophenol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into H₂O (100 ml), extracted with EtOAc (2×50 mL), washed with H₂O (2×50 ml) and brine (50 ml), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(2,4-dichloro-phenoxy)-1-nitrobenzene. The crude product was used for further transformation.

The nitro intermediate (10 mmol) obtained above was dissolved in MeOH (20 mL), and treated with SnCl₂.2H₂O (50 mmol), according to General Procedure I. The reaction mixture was heated under reflux until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo and the residue was treated with 4.0 N aqueous NaOH to pH ˜8. The residue was extracted with EtOAc (2×50 mL), washed with 1.0 N aqueous NaOH (50 mL), brine (50 mL) and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(2,4-dichloro-phenoxy)aniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added. The mesylate prepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched by treating the mixture with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated product was used for further transformation after purifying using silica gel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4.4 mmol) in anhydrous MeOH (10 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 5.3 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a stirred solution of 4-(2,4-dichloro-phenoxy)aniline described above (1.2 eq., 5.2 mmol) in anhydrous DMF (20 mL) DIEA (3 eq. 15 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (4.4 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product obtained from 2-4% MeOH/DCM (yield ˜5%).

To a stirred solution of alkylated 4-(2,4-dichloro-phenoxy)aniline described above (0.2 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 0.6 mmol) was added, followed by slow addition of valeryl chloride (3 eq., 0.6 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to it until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the N-alkylated anilide (0.2 mmol) obtained as above in acetic acid (3 mL), solid ammonium acetate (6 mmol) was added in one portion, according to General Procedure R4. The reaction mixture was then heated to 100° C. overnight. The reaction mixture was cooled to rt, and treated with saturated aqueous sodium bicarbonate solution while stirring to until the pH was 7-8. The contents were extracted with EtOAc (2×15 mL). The combined organic layers was washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired N-aryl imidazole. The crude product was purified using silica gel column chromatography (2-5% MeOH/DCM).

MS m/z 566 (M+H)⁺:

¹H NMR (CDCl₃): δ7.96 (s, 1H), 7.87 (m, 2H), 7.64 (d, 2H), 7.42 (m, 2H), 7.30 (d, 2H), 7.15 (s, 1H), 6.94-6.84 (m, 2H), 4.12 (m, 2H), 3.71-3.42 (m, 6H), 3.14 (m, 2H), 2.29 (t, 2H), 1.59-1.50 (m, 2H), 1.41-1.32 (m, 2H), 1.31 (t, 6H), 0.85 (m, 3H) ppm.

Example 469 [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-5-methyl-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of the 1-[4-(3-diethylamino-propoxy)-phenyl]propane-1-one (1.08 mmol) in anhydrous MeOH (15 mL), pyrrolidone hydrotribromide (1.6 eq.) was added, according to General Procedure R1. The reaction mixture was heated under reflux overnight. The solvent was then removed in vacuuo and the crude alpha-bromophenone was used for further transformation.

To a stirred solution of the above alpha-bromoketone (1.0 eq), 4-(4-chloro-phenoxy)-aniline (1.0 eq) in anhydrous DMF (10 mL) DIEA (1.0 eq) was added. The reaction mixture was stirred under nitrogen at 90° C. until completion, as indicated by HPLC. The reaction mixture was cooled to rt then diluted with Et₂O (100 mL) and washed with sodium bicarbonate (10%, 30 ml), H₂O (2×30 mL), brine (30 mL) and dried with magnesium sulfate. Evaporation of solvent in vacuuo gave a crude oil. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained from 2-7% MeOH/DCM (yield ˜20%).

To a stirred solution of alkylated aniline described above (0.2 mmol) in anhydrous THF (10 mL) at 0° C., DMAP (0.3 eq.) was added, followed by slow addition of valeryl chloride (5.0 eq), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to ambient temperature until completion, as indicated by HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (0.2 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield 66 mg).

MS m/z 546 (M+H)⁺:

¹H NMR (CDCl₃): δ7.59 (d, 2H), 7.35 (d, 2H), 7.19 (d, 2H), 7.08 (d, 2H), 7.03 (d, 2H), 6.93 (d, 2H), 4.02 (t, 2H), 2.51-2.64 (m, 8H), 2.13 (s, 3H), 1.94 (m, 2H), 1.58 (m, 2H), 1.27 (m, 2H), 1.04 (t, 6H), 0.82 (t, 3H) ppm.

Example 470 [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-5-propyl-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of the 1-[4-(3-diethylamino-propoxy)-phenyl]-pentane-1-one (1.08 mmol) in anhydrous MeOH (15 mL), pyrrolidone hydrotribromide (1.6 eq.) was added, according to General Procedure R1. The reaction mixture was heated under reflux overnight. The solvent was then removed in vacuuo and the crude alpha-bromophenone was used for further transformation.

To a stirred solution of the above alpha-bromoketone (1.0 eq), 4-(4-chloro-phenoxy)-aniline (1.0 eq) in anhydrous DMF (10 mL) DIEA (1.0 eq) was added. The reaction mixture was stirred under nitrogen at 90° C. until completion, as indicated by HPLC. The reaction mixture was cooled to rt then diluted with Et₂O (100 mL) and washed with sodium bicarbonate (10%, 30 ml), H₂O (2×30 mL), brine (30 mL) and dried with magnesium sulfate. Evaporation of solvent in vacuuo gave a crude oil. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained from 2-7% MeOH/DCM (yield ˜20%).

To a stirred solution of alkylated aniline described above (0.2 mmol) in anhydrous THF (10 mL) at 0° C., DMAP (0.3 eq.) was added, followed by slow addition of valeryl chloride (5.0 eq), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to ambient temperature until completion, as indicated by HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (0.2 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield 73 mg).

MS m/z 574 (M+H)⁺:

¹H NMR (CDCl₃): δ 7.50 (d, 2H), 7.34 (d, 2H), 7.20 (d, 2H), 7.07 (d, 2H), 7.02 (d, 2H), 6.87 (d, 2H), 4.07 (t, 2H), 3.1-3.2 (m, 6H), 2.40-2.6 (m, 4H), 2.2 (m, 2H), 1.2-1.4 (m, 12H), 0.79 (t, 3H), 0.72 (t, 3H) ppm.

Example 471 [3-(4-{2,5-dibutyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of the 1-[4-(3-diethylamino-propoxy)-phenyl]-hexanane-1-one (1.08 mmol) in anhydrous MeOH (15 mL), pyrrolidone hydrotribromide (1.6 eq.) was added, according to General Procedure R1. The reaction mixture was heated under reflux overnight. The solvent was then removed in vacuuo and the crude alpha-bromophenone was used for further transformation.

To a stirred solution of the above alpha-bromoketone (1.0 eq), 4-(4-chloro-phenoxy)-aniline (1.0 eq) in anhydrous DMF (10 mL) DIEA (1.0 eq) was added. The reaction mixture was stirred under nitrogen at 90° C. until completion, as indicated by HPLC. The reaction mixture was cooled to rt then diluted with Et₂O (100 mL) and washed with sodium bicarbonate (10%, 30 ml), H₂O (2×30 mL), brine (30 mL) and dried with magnesium sulfate. Evaporation of solvent in vacuuo gave a crude oil. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained from 2-7% MeOH/DCM (yield ˜20%).

To a stirred solution of alkylated aniline described above (0.2 mmol) in anhydrous THF (10 mL) at 0° C., DMAP (0.3 eq.) was added, followed by slow addition of valeryl chloride (5.0 eq), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to ambient temperature until completion, as indicated by HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (0.2 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield 67.0 mg).

MS m/z 588 (M+H)⁺:

¹H NMR (CDCl₃): δ 7.54 (d, 2H), 7.36 (d, 2H), 7.24 (d, 2H), 7.09 (d, 2H), 7.03 (d, 2H), 6.90 (d, 2H), 4.07 (t, 2H), 3.2-3.3 (m, 6H), 2.45-2.6 (m, 4H), 2.2 (m, 2H), 1.1-1.6 (m, 14H), 0.8 (t, 3H), 0.70 (t, 3H) ppm.

Example 472 [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-5-ethyl-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of the 1-[4-(3-diethylamino-propoxy)-phenyl]-butane-1-one (1.08 mmol) in anhydrous MeOH (15 mL), pyrrolidone hydrotribromide (1.6 eq.) was added, according to General Procedure R1. The reaction mixture was heated under reflux overnight. The solvent was then removed in vacuuo and the crude alpha-bromophenone was used for further transformation.

To a stirred solution of the above alpha-bromoketone (1.0 eq), 4-(4-chloro-phenoxy)-aniline (1.0 eq) in anhydrous DMF (10 mL) DIEA (1.0 eq) was added. The reaction mixture was stirred under nitrogen at 90° C. until completion, as indicated by HPLC. The reaction mixture was cooled to rt then diluted with Et₂O (100 mL) and washed with sodium bicarbonate (10%, 30 ml), H₂O (2×30 mL), brine (30 mL) and dried with magnesium sulfate. Evaporation of solvent in vacuuo gave a crude oil. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained from 2-7% MeOH/DCM (yield ˜20%).

To a stirred solution of alkylated aniline described above (0.2 mmol) in anhydrous THF (10 mL) at 0° C., DMAP (0.3 eq.) was added, followed by slow addition of valeryl chloride (5.0 eq), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to ambient temperature until completion, as indicated by HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (0.2 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was by elution with 4-6% MeOH/DCM (yield 70 mg).

MS m/z 560 (M+H)⁺:

¹H NMR (CDCl₃): δ7.58 (d, 2H), 7.36 (d, 2H), 7.22 (d, 2H), 7.09 (d, 2H), 7.04 (d, 2H), 6.93 (d, 2H), 4.03 (t, 2H), 2.56 (m, 10H), 1.94 (m, 2H), 1.59 (m, 2H), 1.27 (m, 2H), 1.03 (t, 6H,), 0.97 (t, 3H), 0.82 (t, 3H) ppm.

Example 473 2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-imidazole

To a stirred solution of NaH (3 eq., 6.0 mmol) in DMF (10 mL) at rt, 4′-hydroxyacetophenone (2.2 mmol) was added. The mesylate of 1-(2-hydroxyethyl)-pyrrolidine (prepared from the corresponding alcohol and methanesulfonyl chloride) (2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with saturated sodium bicarbonate (2×15 ml), water (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude alkylated product was purified using silica gel column chromatography. Pure product was obtained with 2-3% MeOH/DCM. (yield 50-60%)

To a stirred solution of the alkoxyacetophenone described above (1 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 1.2 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the residue was treated with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (20 ml) and washed with water (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude alpha-bromoacetophenone was used for further transformation.

To a stirred solution of 4-chloro-phenoxy aniline (1.2 eq., 1.2 mmol) in anhydrous DMF (10 mL) DIEA (3 eq. 3.0 mmol) was added, followed by slow addition of the alpha-bromoacetophenone described above (1.0 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of alkylated aniline described above (1.0 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 3.0 mmol) was added, followed by slow addition of valeryl chloride (2 eq., 2.0 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with water and the product was isolated in DCM. The solvent was removed in vacuuo, and the crude amide was purified using silica gel chromatography. Pure product was obtained from 3-4% MeOH/DCM (Yield 40-45%).

To a stirred solution of the amide described above (0.5 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield: 105 mg).

MS m/z 516 (M)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.69 (d, 2H), 7.34 (d, 2H), 7.29 (d, 2H), 7.09 (s, 1H), 7.05 (m, 4H), 6.95 (d, 2H), 4.19 (t, 2H), 3.05 (t, 2H), 2.84 (m, 4H), 2.77 (t, 2H), 1.89 (m, 4H), 1.65 (m, 2H), 1.34 (m, 2H), 0.85 (t, 3H) ppm

Example 474 1-[2-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-ethyl]-piperidine

To a stirred solution of NaH (3 eq., 6.0 mmol) in DMF (10 mL) at rt, 4′-hydroxyacetophenone (2.2 mmol) was added. The mesylate of 1-(2-hydroxyethyl)-piperidine (prepared from the corresponding alcohol and methanesulfonyl chloride) (2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with saturated sodium bicarbonate (2×15 ml), water (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude alkylated product was purified using silica gel column chromatography. Pure product was obtained with 2-3% MeOH/DCM. (yield 50-60%)

To a stirred solution of the alkoxyacetophenone described above (1 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 1.2 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the residue was treated with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (20 ml) and washed with water (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude alpha-bromoacetophenone was used for further transformation.

To a stirred solution of 4-chloro-phenoxy aniline (1.2 eq., 1.2 mmol) in anhydrous DMF (10 mL) DIEA (3 eq. 3.0 mmol) was added, followed by slow addition of the alpha-bromoacetophenone described above (1.0 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of alkylated aniline described above (1.0 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 3.0 mmol) was added, followed by slow addition of valeryl chloride (2 eq., 2.0 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with water and the product was isolated in DCM. The solvent was removed in vacuuo, and the crude amide was purified using silica gel chromatography. Pure product was obtained from 3-4% MeOH/DCM (Yield 40-45%).

To a stirred solution of the amide described above (0.5 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield: 92 mg).

MS m/z 530 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.49 (d, 2H), 7.34 (d, 2H), 7.15 (d, 2H), 6.97 (s, 1H), 6.93 (m, 4H), 6.84 (d, 2H), 4.18 (t, 2H), 3.33 (m, 4H), 2.81 (t, 2H), 2.68 (t, 2H), 1.67 (m, 2H), 1.55 (m, 2H), 1.37 (m, 2H), 1.02 (m, 4H) 0.65 (t, 3H) ppm

Example 475 [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-2,2-dimethyl-propyl]-dimethyl-amine

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (10 mL) at rt, solid potassium carbonate (8.0 mmol) was added. The mesylate of 3-dimethylamino-2,2-dimethyl-1-propanol (prepared from the corresponding alcohol and methanesulfonyl chloride) (2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was diluted with water and the product was isolated in EtOAc. The combined organic layers were washed with saturated sodium bicarbonate (2×15 ml), water (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude alkylated product was purified using silica gel column chromatography. Pure product was obtained with 2-3% MeOH/DCM. (yield 50-60%)

To a stirred solution of the alkoxyacetophenone described above (1 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 1.2 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the residue was treated with saturated sodium bicarbonate and the product was isolated in EtOAc. The combined organic layers were washed with water (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude alpha-bromoacetophenone was used for further transformation.

To a stirred solution of 4-chloro-phenoxy aniline (1.2 eq., 1.2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 3.0 mmol) was added, followed by slow addition of the alpha-bromoacetophenone described above (1.0 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by

TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of alkylated aniline described above (1.0 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 3.0 mmol) was added, followed by slow addition of valeryl chloride (2 eq., 2.0 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with water and the product was isolated in DCM. The solvent was removed in vacuuo, and the crude amide was purified using silica gel chromatography. Pure product was obtained from 3-4% MeOH/DCM (Yield 40-50%).

To a stirred solution of the amide described above (0.5 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield: 105 mg).

MS m/z 532 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ7.69 (d, 2H), 7.34 (d, 2H), 7.29 (d, 2H), 7.09 (s, 1H), 7.06 (d, 2H), 7.02 (d, 2H), 6.93 (d, 2H), 3.75 (s, 2H), 2.68 (t, 2H), 2.42 (s, 2H), 2.35 (s, 6H), 1.65 (m, 2H), 1.29 (m, 2H), 1.05 (s, 6H), 0.85 (t, 3H) ppm

Example 476 [2-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-ethyl]-diisopropyl-amine

To a stirred solution of 4′-hydroxyacetophenone (2.2 mmol) in DMF (10 mL) at rt, solid potassium carbonate (8.0 mmol) was added. The mesylate of 2-(diisopropylamino)ethanol (prepared from the corresponding alcohol and methanesulfonyl chloride) (2.0 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was diluted with water and the product was isolated in EtOAc. The combined organic layers were washed with saturated sodium bicarbonate (2×15 ml), water (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude alkylated product was purified using silica gel column chromatography. Pure product was obtained with 2-3% MeOH/DCM. (yield 50-60%)

To a stirred solution of the alkoxyacetophenone described above (1 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 1.2 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to it until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the residue was treated with saturated sodium bicarbonate and the product was isolated in EtOAc. The combined organic layers were washed with water (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude alpha-bromoacetophenone was used for further transformation.

To a stirred solution of 4-chloro-phenoxy aniline (1.2 eq., 1.2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 3.0 mmol) was added, followed by slow addition of the alpha-bromoacetophenone described above (1.0 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at it until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of alkylated aniline described above (1.0 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 3.0 mmol) was added, followed by slow addition of valeryl chloride (2 eq., 2.0 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with water and the product was isolated in DCM. The solvent was removed in vacuuo, and the crude amide was purified using silica gel chromatography. Pure product was obtained from 3-4% MeOH/DCM (Yield 40-50%).

To a stirred solution of the amide described above (0.5 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM.

MS m/z 546 (M+H)⁺:

Example 477 [3-(4-{4-[4-(adamantan-1-ylmethoxy)-phenyl]-2-isobutyl-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq., 2.5 mmol) in anhydrous DMF (20 mL) DIEA (3 eq) was added, followed by slow addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone (2.5 mmol). The reaction mixture was stirred under nitrogen at rt until completion, as indicated by HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in Et₂O. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained from 2-7% MeOH/DCM (yield ˜30%).

To a stirred solution of the alkylated aniline described above (0.88 mmol) in anhydrous DCM (10 mL) at 0° C., TEA (3.0 mmol) was added, followed by slow addition of isovaleryl chloride (5.0 eq), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to ambient temperature until completion, as indicated by HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (0.88 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the cyclized product, (crude ˜80%) which was taken to the next transformation without purification.

The above product was dissolved in MeOH (20 mL), Pd/C (100 mg) was added and the heterogeneous mixture was stirred overnight under H₂ atmosphere using a balloon, according to General Procedure T2. The Pd/C was removed by filtration. The solvent was removed in vacuuo, and the crude 4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenol was used for further transformation without purification.

A stirred solution of the 4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenol (1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid sodium hydride (60% dispersion in oil; 1.0 mmol) in portions. After the addition, the mesylate of 1-adamantylmethanol (1.1 eq) was added to the reaction mixture, and stirred at rt overnight, according to General Procedure T3. Et₂O (30 mL) was added to the reaction mixture followed by H₂O (10 mL). The organic layer was washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. The solvent was removed in vacuuo. Pure imidazole was obtained from chromatography with 5-10% MeOH/DCM (yield 60 mg).

MS m/z 570 (M+H)⁺:

¹H NMR (CDCl₃): δ7.68 (d, 2H), 7.20 (d, 2H), 7.09 (s, 1H), 6.97 (d, 2H), 6.90 (d, 2H), 4.06 (t, 2H), 3.5 (s, 2H), 2.6 (t, 2H), 2.58 (q, 4H), 2.52 (d), 1.6-2.1 (m, 18H), 1.05 (t, 6H), 0.85 (d, 6H) ppm.

Example 478 {3-[4-(4-{4-[3-(2,6-dichloro-phenyl)-4-methyl-isoxazol-5-ylmethyloxy]-phenyl}-2-isobutyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

To a stirred solution of N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq., 2.5 mmol) in anhydrous DMF (20 mL) DIEA (3 eq) was added, followed by slow addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone (2.5 mmol). The reaction mixture was stirred under nitrogen at it until completion, as indicated by HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in Et₂O. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained from 2-7% MeOH/DCM (yield ˜30%).

To a stirred solution of the alkylated aniline described above (0.88 mmol) in anhydrous DCM (10 mL) at 0° C., TEA (3.0 mmol) was added, followed by slow addition of isovaleryl chloride (5.0 eq), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to ambient temperature until completion, as indicated by HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (0.88 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the cyclized product, (crude ˜80%) which was taken to the next transformation without purification.

The above product was dissolved in MeOH (20 mL), Pd/C (100 mg) was added and the heterogeneous mixture was stirred overnight under H₂ atmosphere using a balloon, according to General Procedure T2. The Pd/C was removed by filtration. The solvent was removed in vacuuo, and the crude 4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenol was used for further transformation without purification.

To a stirred solution of the 4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenol (1.0 eq) obtained above in anhydrous DMF (5.0 mL) solid sodium hydride (60% dispersion in oil; 1.0 mmol) was added in portions. After the addition, the requisite alkylhalide or the mesylate (prepared from the corresponding alcohol and methanesulfonyl chloride) (1.1 eq) was added to the reaction mixture. The reaction mixture was stirred at rt overnight. Et₂O (30 mL) was added to the reaction mixture followed by H₂O (10 mL). The organic layer was washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. The solvent was removed in vacuuo. Pure product was obtained from 5-10% MeOH/DCM (yield 57 mg).

MS m/z 661 (M+H)⁺:

¹H NMR (CDCl₃): δ 7.65 (d, 2H), 7.2-7.44 (m, 5H), 7.08 (s, 1H), 6.96 (d, 2H), 0.677 (d, 2H), 4.74 (s, 2H), 4.13 (t, 2H), 2.9-3.15 (m, 6H), 2.6 (s, 3H), 2.51 (d, 2H), 2.3 (m, 3H), 1.35 (t, 6H), 0.83 (t, 6H) ppm

Example 479 [3-(4-{4-[4-(4-bromo-benzyloxy)-phenyl]-2-isobutyl-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq., 2.5 mmol) in anhydrous DMF (20 mL) DIEA (3 eq) was added, followed by slow addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone (2.5 mmol). The reaction mixture was stirred under nitrogen at rt until completion, as indicated by HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in Et₂O. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained from 2-7% MeOH/DCM (yield ˜30%).

To a stirred solution of the alkylated aniline described above (0.88 mmol) in anhydrous DCM (10 mL) at 0° C., TEA (3.0 mmol) was added, followed by slow addition of isovaleryl chloride (5.0 eq), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to ambient temperature until completion, as indicated by HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (0.88 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the cyclized product, (crude ˜80%) which was taken to the next transformation without purification.

The above product was dissolved in MeOH (20 mL), Pd/C (100 mg) was added and the heterogeneous mixture was stirred overnight under H₂ atmosphere using a balloon, according to General Procedure T2. The Pd/C was removed by filtration. The solvent was removed in vacuuo, and the crude 4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenol was used for further transformation without purification.

A stirred solution of the 4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenol (1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid sodium hydride (60% dispersion in oil; 1.0 mmol) in portions. The mesylate of (4-bromophenyl)methanol (1.1 eq) was added to the reaction mixture, and stirred at rt overnight, according to General Procedure T3. Et₂O (30 mL) was added to the reaction mixture followed by H₂O (10 mL). The organic layer was washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. The solvent was removed in vacuuo. Pure imidazole was obtained from chromatography with 5-10% MeOH/DCM (yield 95 mg).

MS m/z 591 (M+H)⁺:

¹H NMR (CDCl₃): δ7.7 (d, 2H), 7.5 (d, 2H), 7.32 (d, 2H), 7.21 (d, 2H), 7.11 (s, 1H), 6.96 (m, 4H), 5.03 (s, 2H), 4.07 (t, 2H), 2.5-2.8 (m, 8H), 2.0 (m, 3H), 1.07 (t, 6H), 0.84 (d, 6H) ppm.

Example 480 [3-(4-{2-butyl-1-[4-(6-methoxy-naphthalen-2-yloxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 6-methoxy-2-naphthol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into H₂O (100 mL), extracted with EtOAc (2×50 mL), washed with H₂O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(6-methoxy-naphthalen-2-yloxy)-1-nitrobenzene. The crude product was used for further transformation.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOAc (50 mL) and hydrogenated in the presence of 10% Pd/C (360 mg) until completion according to General Procedure H, as indicated by TLC or HPLC. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-(6-methoxy-naphthalen-2-yloxy)aniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added. The mesylate prepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched by treating the mixture with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated product was used for further transformation after purifying using silica gel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4.6 mmol) in anhydrous MeOH (10 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 5.5 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to it until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a stirred solution of an 4-(6-methoxy-naphthalen-2-yloxy)aniline (5 mmol) in anhydrous DMF (20 mL) DIEA (15 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (4.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at it until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation without additional purification.

To a stirred solution of alkylated 4-(6-methoxy-naphthalen-2-yloxy)aniline described above (4.6 mmol) in anhydrous DCM (10 mL) at 0° C., TEA (3 eq., 15 mmol) was added, followed by slow addition of valeryl chloride (3 eq., 15 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to it until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the N-alkylated anilide (˜4.6 mmol) obtained as above in acetic acid (10 mL), solid ammonium acetate (92 mmol) was added in one portion, according to General Procedure R4. The reaction mixture was then heated to 100° C. overnight. The reaction mixture was cooled to rt, and treated with saturated aqueous sodium bicarbonate solution while stirring to until the pH was 7-8. The contents were extracted with EtOAc (2×40 mL). The combined organic layers was washed with H₂O (2×40 mL) and brine, and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired N-aryl imidazole. The crude product was purified using silica gel column chromatography (2-5% MeOH/DCM) (yield 500 mg).

MS m/z 578 (M+H)⁺:

¹H NMR (CDCl₃): δ8.51 (d, 1H), 8.42 (m, 1H), 8.31 (d, 1H), 7.75 (m, 2H), 7.62 (m, 2H), 7.37 (s, 1H), 7.23 (m, 2H), 7.12 (m, 2H), 7.08 (s, 1H), 6.97-6.79 (m, 2H), 3.98 (t, 2H), 3.41 (s, 3H), 3.23-3.05 (m, 6H), 2.75 (m, 2H), 2.45 (m, 2H), 1.75-1.48 (m, 4H), 1.37 (t, 6H), 0.80 (m, 3H) ppm.

Example 481 [3-(4-{2-butyl-1-[4-(naphthalen-2-yloxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 2-naphthol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into H₂O (100 mL), extracated with EtOAc (2×50 mL), washed with H₂O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(naphthalen-2-yloxy)-1-nitrobenzene. The crude product was used for further transformation.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOH (50 mL) and hydrogenated in the presence of 10% Pd/C (300 mg) until completion according to General Procedure H, as indicated by TLC or HPLC. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-(naphthalen-2-yloxy)aniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added. The mesylate prepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched by treating the mixture with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated product was used for further transformation after purifying using silica gel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4.6 mmol) in anhydrous MeOH (10 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 5.5 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a stirred solution of 4-(naphthalen-2-yloxy)aniline (1.2 eq., 5 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 15 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (4.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at it until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation without additional purification.

To a stirred solution of alkylated 4-(naphthalen-2-yloxy)aniline described above (4.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 15 mmol) was added, followed by slow addition of valeryl chloride (3 eq., 15 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to it until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the N-alkylated anilide (˜4.6 mmol) obtained as above in acetic acid (10 mL), solid ammonium acetate (92 mmol) was added in one portion, according to General Procedure R4. The reaction mixture was then heated to 100° C. overnight. The reaction mixture was cooled to rt, and treated with saturated aqueous sodium bicarbonate solution while stirring to until the pH was 7-8. The contents were extracted with EtOAc (2×50 mL). The combined organic layers was washed with H₂O (50 mL) and brine, and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired N-aryl imidazole. The crude product was purified using silica gel column chromatography (2-5% MeOH/DCM) (yield 170 mg).

MS m/z 548 (M+H)⁺:

¹H NMR (CDCl₃): δ7.91 (t, 1H), 7.84 (t, 1H), 7.77 (m, 1H), 7.71 (m, 2H) 7.56-7.42 (m, 4H), 7.32 (m, 2H), 7.18 (s, 1H), 7.16-7.03 (m, 2H), 7.00-6.86 (m, 2H), 4.02 (t, 2H), 3.00-2.76 (m, 6H), 2.70 (m, 2H), 2.12 (m, 2H), 1.44-1.28 (m, 4H), 1.23 (t, 6H), 0.93 (m, 3H) ppm.

Example 482 2-butyl-4-[4-(4-ethyl-hexyloxy)-phenyl]-1-[4-(4-methoxy-naphthalen-1-yl-oxy)-phenyl]-1H-imidazole

To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 4-methoxy-1-naphthol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into H₂O (100 mL), extracted with EtOAc (2×50 mL), washed with H₂O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(4-methoxynaphthalen-1-yloxy)-1-nitrobenzene. The crude product was used for further transformation.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOAc (50 mL) and hydrogenated in the presence of 10% Pd/C (360 mg) until completion according to General Procedure H, as indicated by TLC or HPLC. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-(4-methoxy-naphthalen-1-yloxy)aniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added. The mesylate prepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched by treating the mixture with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated product was used for further transformation after purifying using silica gel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2.3 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.7 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to it until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a stirred solution of 4-(4-methoxy-naphthalen-1-yloxy)aniline (1.2 eq., 2.5 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 7.5 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (2.3 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at it until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of alkylated 4-(4-methoxynaphthalen-1-yloxy)aniline described above (2.3 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 7.5 mmol) was added, followed by slow addition of valeryl chloride (3 eq., 7.5, mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the N-alkylated anilide (2.3 mmol) obtained as above in acetic acid (5 mL), solid ammonium acetate (46 mmol) was added in one portion, according to General Procedure R4. The reaction mixture was then heated to 100° C. overnight. The reaction mixture was cooled to rt, and treated with saturated aqueous sodium bicarbonate solution while stirring to until the pH was 7-8. The contents were extracted with EtOAc (2×30 mL). The combined organic layers was washed with H₂O (2×30 mL) and brine, and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired N-aryl imidazole. The crude product was purified using silica gel column chromatography (2-5% MeOH/DCM) (yield 213 mg).

MS m/z 578 (M+H)⁺:

¹H NMR (CDCl₃): δ8.35 (dd, 1H), 7.60 (dd, 1H), 7.72 (m, 2H), 7.55 (m, 2H), 7.24 (s, 1H), 7.23 (m, 2H), 7.15 (t, 1H), 7.04 (m, 2H), 6.90 (m, 2H), 6.80 (d, 1H), 4.04 (s, 3H), 3.95 (t, 2H), 3.00-2.87 (m, 6H), 2.67 (t, 2H), 2.10 (m, 2H), 1.65 (m, 2H), 1.38 (m, 2H), 1.21 (t, 6H), 0.95 (m, 3H) ppm.

Example 483 [3-(4-{2-butyl-1-[4-(dibenzofuran-2-yloxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 2-hydroxydibenzofuran (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into H₂O (100 mL), extracted with EtOAc (2×50 mL), washed with H₂O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(dibenzofuran-2-yloxy)-1-nitrobenzene. The crude product was used for further transformation.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOAc (50 mL) and hydrogenated in the presence of 10% Pd/C (360 mg) until completion according to General Procedure H, as indicated by TLC or HPLC. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-(dibenzofuran-2-yloxy)aniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added. The mesylate prepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched by treating the mixture with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated product was used for further transformation after purifying using silica gel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2.3 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq, 2.7 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to it until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a stirred solution of 4-(dibenzofuran-2-yloxy)aniline (1.2 eq., 2.5 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 7.5 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (2.3 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at it until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of alkylated 4-(dibenzofuran-2-yloxy)aniline described above (˜2.3 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 7.5 mmol) was added, followed by slow addition of valeryl chloride (3 eq., 7.5 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to it until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the N-alkylated anilide (2.3 mmol) obtained as above in acetic acid (5 mL), solid ammonium acetate (46 mmol) was added in one portion, according to General Procedure R4. The reaction mixture was then heated to 100° C. overnight. The reaction mixture was cooled to rt, and treated with saturated aqueous sodium bicarbonate solution while stirring to until the pH was 7-8. The contents were extracted with EtOAc (2×30 mL). The combined organic layers was washed with H₂O (2×30 mL) and brine, and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired N-aryl imidazole. The crude product was purified using silica gel column chromatography (2-5% MeOH/DCM) (yield 164 mg).

MS m/z 588 (M+H)⁺:

¹H NMR (CDCl₃): δ7.92 (d, 1H), 7.71 (m, 2H), 7.62 (d, 2H), 7.51 (t, 1H), 7.37 (t, 1H), 7.32-7.26 (m, 3H), 7.23 (m, 2H), 7.16 (s, 1H), 7.13-7.09 (m, 1H), 6.91 (d, 2H), 4.08 (t, 2H), 2.97-2.75 (m, 6H), 2.69 (t, 2H), 2.19 (m, 2H), 1.69 (m, 2H), 1.39-1.25 (m, 2H), 1.29 (t, 6H), 0.89 (t, 3H) ppm.

Example 484 6-(4-{2-butyl-4-[4-(3-diethylamino-propoxy)-phenyl]-imidazol-1-yl}-phenoxy)-naphthalen-2-ol

To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 6-methoxy-2-naphthol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into H₂O (100 mL), extracted with EtOAc (2×50 mL), washed with H₂O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(6-methoxy-2-naphthalen-2-yloxy)-1-nitrobenzene. The crude product was used for further transformation.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOAc (50 mL) and hydrogenated in the presence of 10% Pd/C (360 mg) until completion according to General Procedure H, as indicated by TLC or HPLC. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-(6-methoxy-naphthalen-2-yloxy)aniline, which was used directly for further transformation without additional purification.

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added. The mesylate prepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched by treating the mixture with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated product was used for further transformation after purifying using silica gel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4.6 mmol) in anhydrous MeOH (10 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 5.2 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a stirred solution of an 4-(6-methoxy-naphthalen-2-yloxy)aniline (5 mmol) in anhydrous DMF (20 mL) DIEA (15 mmol) was added, followed by slow addition of the 2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone described above (4.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation without additional purification.

To a stirred solution of alkylated 4-(6-methoxy-2-naphthalenoxy)aniline described above (4.6 mmol) in anhydrous DCM (10 mL) at 0° C., TEA (3 eq., 15 mmol) was added, followed by slow addition of valeryl chloride (3 eq., 15 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the N-alkylated anilide (˜4.6 mmol) obtained as above in acetic acid (10 mL), solid ammonium acetate (92 mmol) was added in one portion, according to General Procedure R4. The reaction mixture was then heated to 100° C. overnight. The reaction mixture was cooled to rt, and treated with saturated aqueous sodium bicarbonate solution while stirring to until the pH was 7-8. The contents were extracted with EtOAc (2×40 mL). The combined organic layers was washed with H₂O (2×40 mL) and brine, and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired N-aryl imidazole. The crude product was purified using silica gel column chromatography (2-5% MeOH/DCM) (Yield: 19%).

The N-aryl imidazole (0.12 mmol) previously described was dissolved in 5 mL of 48% aqueous HBr and heated to 90° C. for 36 h until the reaction was complete by HPLC. The reaction mixture was cooled to rt and treated with ice-cold saturated aqueous sodium bicarbonate solution until pH 8. The mixture was extracted with EtOAc (2×15 mL). The combined organic layers was washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the demethylated N-aryl imidazole. The crude product was purified using silica gel column chromatography (2-5% MeOH/DCM) (yield 20 mg).

MS m/z 564 (M+H)⁺:

¹H NMR (CDCl₃): δ7.62 (d, 2H), 7.60 (s, 1H), 7.58-7.54 (m, 2H), 7.32 (d, 1H), 7.18 (s, 1H), 7.16 (d, 1H), 7.15-7.10 (m, 2H), 7.08 (s, 1H), 7.02 (d, 2H), 6.78 (d, 2H), 3.95 (t, 2H), 3.00-2.81 (m, 6H), 2.60 (t, 2H), 2.12 (m, 2H), 1.56 (m, 2H), 1.30 (t, 2H), 1.21 (t, 6H), 0.75 (t, 3H) ppm.

Example 485 [3-(4-{2-butyl-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

A mixture of 4-fluoroacetophone (50 mmol), 4-chlorophenol (75 mmol, 1.5 eq), cesium carbonate (150 mmol, 3 eq) and anhydrous DMSO (80 mL) was heated with stirring at 90° C. for 20 h (monitored by TLC). After cooling to rt, the reaction mixture was treated with cold H₂O (150 mL), and the resulting mixture was extracted with ether (4×100 mL). The combined organic layers were washed with 2N NaOH (4×100 mL), H₂O (2×100 mL) and brine (100 mL), and dried over anhydrous sodium sulfate. The crude 1-[4-(4-chlorophenoxy)phenyl]ethanone was purified by flash chromatography (eluting with 5-10% EtOAc in hexane) to give 4-(4′-chlorophenoxy)acetophone as an almost colorless solid (yield: 80%).

To a stirred solution of 4-fluoronitrobenzene (50 mmol) and 3-diethylaminoproanol (70 mmol) dissolved in anhydrous THF (50 mL) at 0° C. and under a nitrogen stream was added KOBu^(t) (70 mmol) in portions, and the reaction mixture was allowed to warm to rt, and stirred overnight, according to General Procedure L1. The reaction mixture was then treated with cold H₂O (80 mL), and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×60 mL) and dried over anhydrous sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine, which was used for further transformation without further purification (yield: ˜98%).

The crude N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (˜33 mmol) was dissolved in MeOH (50 mL), and hydrogenated in the presence of 10% Pd/C (0.8 g) until the reaction was complete as indicated by LC-MS (˜4 h), according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed under high vacuum to afford N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine which was used directly for further transformation without further purification (yield: ˜96%).

1-[4-(4-chlorophenoxy)phenyl]ethanone (24 mmol) was dissolved in 1,4-dioxane (100 mL), and pyridine hydrotribromide (25.2 mmol, 1.05 eq) was added, according to General Procedure R1. After being stirred at rt for 7 h (monitored by TLC), the reaction was quenched with cold H₂O (100 mL). The resulting mixture was extracted with ether (4×100 mL). The combined ether extracts were washed with brine (3×50 mL), and dried over anhydrous sodium sulfate. The solvent was then removed in vacuuo and the crude 2-bromo-1-[4-(4-chlorophenoxy)phenyl]ethanone was directly used for further transformation.

To a stirred solution of ice-cold N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (22 mmol, 1.1 eq) dissolved in DCM (40 mL) was added dropwise a solution of the 2-bromo-1-[4-(4-chlorophenoxy)phenyl]ethanone (20 mmol) dissolved in DMF (30 mL), according to General Procedure R2. The mixture was stirred at 0° C. for 3 h, and then allowed to warm to rt, continuing the stirring for additional 2 h (monitored by LC-MS). The reaction mixture was treated with saturated sodium bicarbonate (100 mL), and the resulting mixture was extracted with EtOAc (4×100 mL). The combined EtOAc extracts were washed with brine (3×50 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude product was purified by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (overall yield from 1-[4-(4-chlorophenoxy)phenyl]ethanone: 60%).

To a stirred solution of the alkylated aniline described above (10 mmol) dissolved in anhydrous DCM (100 mL) at 0° C., TEA (40 mmol, 4 eq) was added, followed by a slow addition of valeryl chloride (20 mmol, 2 eq), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 2 h and allowed to warm to rt until completion, as indicated by LC-MS. The solvent was removed in vacuuo, and the crude amide was used directly for further transformation.

The crude amide described above (˜6 mmol) was suspended in acetic acid (10 mL), and ammonium acetate (excess, ˜30 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. for 6 h (as monitored by LC-MS). The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate and solid sodium carbonate. The resulting mixture was extracted with EtOAc (4×100 mL). The combined EtOAc extracts were washed with H₂O (2×60 mL) and brine (2×60 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude product was purified by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA affording Example 485.

MS m/z 532 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ0.83 (t, 3H), 1.04 (t, 6H), 1.28 (m, 2H), 1.63 (m, 2H), 1.96 (m, 2H), 2.56 (q, 4H), 2.61-2.65 (m, 4H), 4.06 (t, 2H), 6.93 (d, 2H), 6.98 (d, 2H), 7.00 (d, 2H), 7.16 (s, 1H), 7.22 (d, 2H), 7.26 (d, 2H), 7.76 (d, 2H) ppm.

Example 486 [3-(4-{2-(4-tert-butyl-cyclohexyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (80 mmol) in MeOH (200 mL) at rt, pyrrolidone hydrotribromide (96 mmol, 1.2 eq) was added in portions at rt, according to General Procedure R1. The reaction mixture was stirred at rt for 2 h (monitored by LC-MS). The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was directly used for further transformation.

The solution of the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone dissolved in anhydrous DMF (180 mL) was chilled to 0° C., and 4-(4′-chlorophenoxy)aniline (88 mmol, 1.1 eq) was added, followed by slowly adding DIEA (240 mmol, 3 eq), according to General Procedure R2. After being stirred at 0° C. for 1 h and at rt for additional 4 h, the reaction mixture was treated with saturated sodium bicarbonate (250 mL). The resulting mixture was extracted with EtOAc (4×200 mL). The combined EtOAc extracts were washed with brine (3×100 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude product was purified by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA.

Oxayl chloride (420 mmol, 3 eq) was added slowly to an ice-cold solution of 4-t-butylcyclohexanecarboxylic acid (140 mmol) dissolved in anhydrous DCM (80 mL), and the reaction mixture was stirred at 0° C. for 3 h and at rt for additional 3 h. The solvent was removed in vacuuo, and the resulting acid chloride was pumped under high vacuum for about 30 min, and used for next step reaction without further purification.

To a stirred solution of the 2-[4-(4-chlorophenoxy)-phenylamino]-1-[4-(3-diethylamino-propoxy)-phenyl]-ethanone described above (35 mmol) dissolved in anhydrous DCM (200 mL) at 0° C., TEA (140 mmol, 4 eq) was added, followed by a slow addition of the freshly prepared acid chloride (70 mmol, 2 eq). The reaction mixture was stirred under nitrogen at 0° C. for 2 h and allowed to warm to it until completion, as indicated by LC-MS. The solvent was removed in vacuuo, and the crude amide was used directly for further transformation.

The crude amide described above (˜35 mmol) was suspended in acetic acid (50 mL), and ammonium acetate (excess, ˜30 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 100° C. for 6 h (as monitored by LC-MS). The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate and solid sodium carbonate. The resulting mixture was extracted with EtOAc (4×200 mL). The combined EtOAc extracts were washed with H₂O (2×100 mL) and brine (2×100 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude product was purified by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA affording the title compound as cis/trans (1:2 ratio) mixture (yield 14.5 g).

LC: 1.06 min; MS: m/z 614 (M+H)⁺

Example 487 [3-{4-[1-[4-(4-chloro-phenoxy)-phenyl]-2-(4-ethyl-cyclohexyl)-1H-imidazol-4-yl]-phenoxy}-propyl)-diethyl-amine

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (80 mmol) in MeOH (200 mL) at rt, pyrrolidone hydrotribromide (96 mmol, 1.2 eq) was added in portions at rt, according to General Procedure R1. The reaction mixture was stirred at rt for 2 h (monitored by LC-MS). The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was directly used for further transformation.

The solution of the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone dissolved in anhydrous DMF (180 mL) was chilled to 0° C., and 4-(4′-chlorophenoxy)aniline (88 mmol, 1.1 eq) was added, followed by slowly adding DIEA (240 mmol, 3 eq), according to General Procedure R2. After being stirred at 0° C. for 1 h and at rt for additional 4 h, the reaction mixture was treated with saturated sodium bicarbonate (250 mL). The resulting mixture was extracted with EtOAc (4×200 mL). The combined EtOAc extracts were washed with brine (3×100 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude product was purified by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield: 45%).

Oxayl chloride (3 mmol, 3 eq) was added slowly to an ice-cold solution of trans-4-ethylcyclohexanecarboxylic acid (1 mmol) dissolved in anhydrous DCM (5 mL), and the reaction mixture was stirred at 0° C. for 2 h and at rt for additional 1 h. The solvent was removed in vacuuo, and the resulting acid chloride was pumped under high vacuum for about 30 min, and used without further purification.

To a stirred solution of the 2-[4-(4-chlorophenoxy)-phenylamino]-1-[4-(3-diethylamino-propoxy)-phenyl]-ethanone (0.3 mmol) described above dissolved in anhydrous DCM (10 mL) at 0° C., TEA (1.2 mmol, 4 eq) was added, followed by slow addition of the freshly prepared acid chloride (˜1 mmol, ˜3 eq). The reaction mixture was stirred under nitrogen at 0° C. for 2 h and allowed to warm to rt until completion, as indicated by LC-MS. The solvent was removed in vacuuo, and the crude amide was used directly for further transformation.

To a stirred solution of the amide described above (˜0.3 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜30 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 100° C. for 3 h (as monitored by LC-MS). The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate. The resulting mixture was extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with brine (3×20 ml), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the pure product was obtained by silica gel column chromatography eluting with 10% MeOH/EtOAc+0.2% Et₃N (yield 123 mg).

MS m/z 586 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ0.85 (t, 3H), 1.06 (t, 6H), 1.16-1.82 (m, 12H), 1.96 (m, 2H), 2.61 (q, 4H), 2.68 (t, 2H), 4.01 (t, 2H), 6.89 (d, 2H), 7.03 (d, 2H), 7.06 (d, 2H), 7.08 (s, 1H), 7.27 (d, 2H), 7.35 (d, 2H), 7.68 (d, 2H) ppm.

Example 488 [4-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-phenyl]-(1-ethyl-piperidin-4-ylmethyl)-amine

To a stirred solution of the 4′-(4-nitro-phenoxy)acetophenone (2 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the residue was treated with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (20 ml) and washed with water (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude alpha-bromoacetophenone was used for further transformation.

To a stirred solution of the 4-chloro-phenoxy aniline (1.2 eq., 2.2 mmol) in anhydrous DMF (10 mL) DIEA (3 eq. 6 mmol) was added, followed by slow addition of the alpha-bromoacetophenone described above (1.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of alkylated aniline described above (1.6 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 4.8 mmol) was added, followed by slow addition of valeryl chloride (2 eq., 3.2 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with water and the product was isolated in DCM. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to it and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the cyclized imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 30-40% ethylacetate/hexane (yield 50-55%).

The cyclized imidazole intermediate obtained above (0.5 mmol) obtained above was dissolved in MeOH (5 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired reduced imidazole, which was used directly for further transformation without further purification.

To a stirred solution of N-Boc-4-piperidineacetic acid (1.2 eq., 0.6 mmol) in anhydrous DCM (2 mL) was added DCC-PS (1.5 eq., 0.75 mmol). The solution was allowed to shake at rt for 20-30 min. This was followed by addition of the reduced cyclized imidazole described above (0.5 mmol). The reaction mixture was shaken overnight at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then filtered and the product was isolated in DCM. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (0.5 mmol) in anhydrous THF (2 mL) at 0° C., borane/THF (3 eq, 1.5 mmol) was added. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The reaction mixture was then cooled to rt and the solvent was removed in vacuuo to give the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 3-4% MeOH/DCM (yield 150 mg).

MS m/z 635 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ 8.01 (s, 1H), 7.84 (d, 2H), 7.65 (d, 2H), 7.59 (d, 2H), 7.44 (d, 2H), 7.22 (m, 6H), 7.12 (d, 2H), 3.65 (d, 2H), 3.45 (d, 2H), 3.03 (t, 2H), 3.18 (m, 2H), 2.98 (m, 4H), 2.15 (m, 2H), 1.71 (m, 3H), 1.39 (m, 5H), 0.85 (t, 3H) ppm

Example 489 [4-{1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-(3-diethylaminopropoxy)-phenyl]-1H-imidazol-2-yl}-butyric acid methyl ester

As described in Example 406, 2-[4-(4-chlorophenoxy)-phenylamino]-1-[4-(3-diethylamino-propoxy)-phenyl]-ethanone (0.5 mmol) was dissolved in anhydrous DCM (10 mL) and cooled to 0° C. TEA (2 mmol, 4 eq) was added to the reaction mixture, followed by slow addition of methyl 4-(chloroformyl)butyrate (1.5 mmol, 3 eq), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 2 h and allowed to warm to rt until completion, as indicated by LC-MS. The solvent was removed in vacuuo, and the crude amide was used directly for further transformation.

To a stirred solution of the amide described above in acetic acid (2 mL), ammonium acetate (excess, ˜30 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 100° C. for 3 h (as monitored by LC-MS). The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate. The resulting mixture was extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with brine (3×20 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the pure product was obtained by silica gel column chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield: ˜70%) (yield 202 mg).

MS m/z 576 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ1.04 (t, 6H), 1.94 (m, 2H), 2.02 (m, 2H), 2.39 (t, 2H), 2.56 (q, 4H), 2.63 (t, 2H), 2.72 (t, 2H), 3.59 (s, 3H), 4.02 (t, 2H), 6.91 (d, 2H), 7.03 (d, 2H), 7.07 (d, 2H), 7.14 (s, 1H), 7.29 (d, 2H), 7.35 (d, 2H), 7.68 (d, 2H) ppm.

Example 490 [3-(4-{2-butyl-1-[4-(4-chloro-2-cyclohexyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (10 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 4-chloro-2-cyclohexylphenol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into EtOAc (80 ml), washed with H₂O (2×40 ml) and brine (60 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(4-chloro-2-cyclohexylphenoxy)-1-nitrobenzene. The crude product was used for further transformation.

The nitro intermediate (10 mmol) obtained above was dissolved in MeOH (20 mL), and treated with SnCl₂.2H2O (50 mmol), according to General Procedure I. The reaction mixture was heated under reflux until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo and the residue was treated with 4.0 N aqueous NaOH to pH ˜8. The residue was extracted with EtOAc (2×50 mL), washed with 1.0 N aqueous NaOH, brine and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(4-chloro-2-cyclohexylphenoxy) aniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added. The mesylate prepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched by treating the mixture with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated product was used for further transformation after purifying using silica gel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2.4 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq, 2.9 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to it until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a stirred solution of 4-(4-chloro-2-cyclohexylphenoxy) aniline (1.2 eq., 2.5 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (2.4 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at it until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product obtained from 2-4% MeOH/DCM (yield ˜50-60%).

To a stirred solution of alkylated 4-(4-chloro-2-cyclohexylphenoxy) aniline described above (2.4 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 7.5 mmol) was added, followed by slow addition of valeryl chloride (3 eq., 7.5 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the N-alkylated anilide (˜2.4 mmol) obtained as above in acetic acid (5 mL), solid ammonium acetate (46 mmol) was added in one portion, according to General Procedure R4. The reaction mixture was then heated to 100° C. overnight. The reaction mixture was cooled to rt, and treated with saturated aqueous sodium bicarbonate solution while stirring to until the pH was 7-8. The contents were extracted with EtOAc (2×30 mL). The combined organic layers was washed with H₂O (2×30 mL) and brine, and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired N-aryl imidazole. The crude product was purified using silica gel column chromatography (2-5% MeOH/DCM) (yield 118 mg).

MS m/z 614 (M+H)⁺:

¹H NMR (CDCl₃) δ7.86 (d, 1H), 7.63 (d, 2H), 7.25 (d, 2H), 7.18 (s, 1H), 7.08 (s, 1H), 6.94 (d, 2H), 6.81 (d, 2H), 6.80 (d, 1H, 6.8 Hz), 4.12 (m, 2H), 3.20 (m, 2H), 2.98-2.79 (m, 6H), 2.60 (t, 2H), 2.21-2.19 (m, 2H), 2.15-2.05 (m, 1H), 1.78-1.72 (m, 2H), 1.59-1.50 (m, 2H), 1.36-1.24 (m, 4H), 1.21 (t, 6H), 0.84 (m, 4H), 0.79 (m, 3H) ppm.

Example 491 [3-(4-{1-[4-(biphenyl-4-yloxy)-phenyl]-2-butyl-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at room temperature, solid K₂CO₃ (30 mmol) was added followed by addition of 4-hydroxybiphenyl (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to room temperature to room temperature, the reaction mixture was poured into EtOAc (100 mL), washed with water (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuo to afford the desired 4-(biphenyl-4-oxy)-1-nitrobenzene. The crude product was used for further transformation.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOAc (40 mL) and hydrogenated in the presence of 10% Pd/C (360 mg) until completion, as indicated by TLC or HPLC. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuo to afford the desired 4-(biphenyl-4-oxy)aniline, which was used directly for further transformation without further purification.

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL) at room temperature, solid K₂CO₃ (153 mmol) was added. The mesylate of 3-diethylamino-1-propanol and methanesulfonyl chloride (76 mmol) was added to the reaction mixture and heated to 80° C. until completion, as indicated by TLC or HPLC. After cooling to room temperature, the reaction mixture was quenched by treating the mixture with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (100 mL) and washed with water (2×50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, and the solvent was removed in vacuuo to afford the desired product. The crude alkylated product was used for further transformation after purifying using silica gel column chromatography (1-4% methanol/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2.4 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.9 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a stirred solution of 4-(biphenyl-4-oxy)aniline (1.2 eq., 2.5 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (2.4 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product obtained from 2-4% MeOH/DCM (yield ˜13%).

To a stirred solution of alkylated 4-(biphenyl-4-oxy)aniline described above (0.3 mmol) in anhydrous DCM (3 mL) at 0° C., TEA (3 eq., 0.9 mmol) was added, followed by slow addition of valeryl chloride (3 eq., 0.9 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the N-alkylated anilide (˜0.3 mmol) obtained as above in acetic acid (3 mL), solid ammonium acetate (6 mmol) was added in one portion, according to General Procedure R4. The reaction mixture was then heated to 100° C. overnight. The reaction mixture was cooled to rt, and treated with saturated aqueous sodium bicarbonate solution while stirring to until the pH was 7-8. The contents were extracted with EtOAc (2×15 mL). The combined organic layers was washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired N-aryl imidazole. The crude product was purified using silica gel column chromatography (2-5% MeOH/DCM).

MS m/z 574 (M+H)⁺

¹H NMR (CDCl₃) δ7.86 (d, 1H), 7.63 (d, 2H), 7.25 (d, 2H), 7.18 (s, 1H), 7.08 (s, 1H), 6.94 (d, 2H), 6.81 (d, 2H), 6.80 (d, 1H), 4.12 (m, 2H), 3.20 (m, 2H), 2.98-2.79 (m, 6H), 2.60 (t, 2H), 2.21-2.19 (m, 2H), 2.15-2.05 (m, 1H), 1.78-1.72 (m, 2H), 1.59-1.50 (m, 2H), 1.36-1.24 (m, 4H), 1.21 (t, 6H), 0.84 (m, 4H), 0.79 (m, 3H) ppm

Example 492 [3-(4-{1-[4-(4-bromo-phenoxy)-phenyl]-2-butyl-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 4-bromophenol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into EtOAc (100 mL), washed with H₂O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-bromophenoxy-1-nitrobenzene. The crude product was used for further transformation.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOAc (50 mL) and hydrogenated in the presence of 10% Pd/C (360 mg) until completion according to General Procedure H, as indicated by TLC or HPLC. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-bromophenoxyaniline, which was used directly for further transformation without additional purification.

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added. The mesylate prepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched by treating the mixture with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated product was used for further transformation after purifying using silica gel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2.4 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.9 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a stirred solution of 4-bromophenoxyaniline (1.2 eq., 2.5 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 7.5 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (2.4 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product obtained from 2-4% MeOH/DCM.

To a stirred solution of alkylated 4-bromophenoxyaniline described above (0.45 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 1.35 mmol) was added, followed by slow addition of valeryl chloride (3 eq., 1.35 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the N-alkylated anilide (˜0.45 mmol) obtained as above in acetic acid (3 mL), solid ammonium acetate (9 mmol) was added in one portion, according to General Procedure R4. The reaction mixture was then heated to 100° C. overnight. The reaction mixture was cooled to rt, and treated with saturated aqueous sodium bicarbonate solution while stirring to until the pH was 7-8. The contents were extracted with EtOAc (2×15 mL). The combined organic layers was washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired N-aryl imidazole. The crude product was purified using silica gel column chromatography (2-5% MeOH/DCM) (yield 66 mg).

MS m/z 577 (M+H)⁺:

¹H NMR (CDCl₃): δ7.63 (d, 2H), 7.43 (d, 2H), 7.23 (d, 2H), 7.08 (s, 1H), 7.02 (d, 2H), 6.90 (d, 2H), 6.83 (d, 2H) 4.05 (t, 2H), 2.92-2.72 (m, 6H), 2.60 (t, 2H), 2.05-2.15 (m, 2H), 1.60 (m, 2H), 1.33 (m, 2H), 1.20 (t, 6H), 0.80 (t, 3H) ppm

Example 493 N-[4-(4-{2-butyl-4-[4-(3-diethylamino-porpoxy)-phenyl]-imidazol-1-yl}-phenoxy)-phenyl]-acetamide

3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM (25 mL), TEA (40 mmol, 2 eq) was added and the mixture was cooled to 0° C. To this mixture, methanesulfonyl chloride (30 mmol, 1.5 eq) was added slowly with stirring and the reaction mixture was stirred at 0° C. for 1 h and at rt for 1 h (until the reaction was complete by HPLC). The solvent was removed and to this saturated aqueous sodium bicarbonate was added. The product was extracted with EtOAc (3×) and washed with sodium bicarbonate and water. The solvent was removed in vacuuo.

The mesylate from the previous step (20 mmol, 1 eq) was dissolved in anhydrous DMF (25 mL) to which 4-hydroxyacetophenone (20 mmol, 1 eq) and potassium carbonate (60 mmol, 3 eq) were added. The mixture was heated under reflux at 85° C. for 18 h (until the reaction was complete by HPLC), after which it was cooled to rt. Saturated aqueous sodium bicarbonate was added to the mixture, which was then transferred to a separatory funnel. The product was extracted with EtOAc and washed with sodium bicarbonate and water. The solvent was removed in vacuuo and the product 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by flash chromatography (going by increasing gradient up to 10% MeOH in DCM). The overall yield was 60%.

4-Acetamidophenol (10 mmol) was dissolved in 15 ml of anhydrous DMF and potassium carbonate (30 mmol) was added with stirring at rt. 4-Fluoronitrobenzene (10 mmol) was added to this mixture, which was then heated under reflux at 80° C. for 18 h. The reaction was quenched with 30 ml of water and 30 ml of sodium bicarbonate, extracted with EtOAc (3×50 ml) and washed with sodium bicarbonate and water. EtOAc layer was dried over anhydrous sodium sulfate and filtered, after which the solvent was removed in vacuuo.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOH (30 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion according to General Procedure H, as indicated by TLC or HPLC. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-(3,4-dichlorophenoxy)aniline, which was used directly for further transformation without further purification (yield 80%).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (6 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a solution of 4-(4-acetamidophenoxy) aniline (1 eq, 2 mmol) in anhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was added, followed by addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (2 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product obtained from 2-4% MeOH/DCM (yield 54%).

To a stirred solution of alkylated aniline described above (1 mmol) in anhydrous DCM (4 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed by a slow addition of valeryl chloride (3 eq, 3 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1 mmol) in acetic acid (4 mL), ammonium acetate (20 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield 210 mg).

MS m/z 555 (M+H)⁺:

¹H NMR: (CDCl₃): δ7.68 (d, 2H), 7.51 (d, 2H), 7.25 (d, 2H), 7.13 (s, 1H), 6.88-7.00 (m, 6H), 4.02 (t, 2H), 2.62-2.70 (m, 8H), 2.20 (s, 3H), 2.16 (m, 2H), 1.97 (m, 2H), 1.16 (m, 2H), 1.05 (t, 6H), 0.83 (t, 3H) ppm

Example 494 (3-{4-[2-butyl-1-(4-p-tolyloxy-phenyl)-1H-imidazol-4-yl]-phenoxy}-propyl)-diethyl-amine

3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM (25 mL), TEA (40 mmol, 2 eq) was added and the mixture was cooled to 0° C. To this mixture, methanesulfonyl chloride (30 mmol, 1.5 eq) was added slowly with stirring and the reaction mixture was stirred at 0° C. for an hour and at rt for another hour (until the reaction was complete by HPLC). The solvent was removed and to this saturated aqueous sodium bicarbonate was added. The product was extracted with EtOAc (3×) and washed with sodium bicarbonate and water. The solvent was removed in vacuuo.

The mesylate from the previous step (20 mmol, 1 eq) was dissolved in anhydrous DMF (25 mL) to which 4-hydroxyacetophenone (20 mmol, 1 eq) and potassium carbonate (60 mmol, 3 eq) were added. The mixture was heated under reflux at 85° C. for 18 h (until the reaction was complete by HPLC), after which it was cooled to rt. Saturated aqueous sodium bicarbonate was added to the mixture, which was then transferred to a separatory funnel. The product was extracted with EtOAc and washed with sodium bicarbonate and water. The solvent was removed in vacuuo and the product 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by flash chromatography (going by increasing gradient up to 10% MeOH in DCM). The overall yield was 60%.

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (6 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC.

The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a solution of 4-tolyloxy aniline (1 eq, 2 mmol) in anhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was added, followed by addition of the 2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone described above (2 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product obtained from 2-4% MeOH/DCM (yield 56%).

To a stirred solution of alkylated aniline described above (1 mmol) in anhydrous DCM (4 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed by a slow addition of valeryl chloride (3 eq, 3 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1 mmol) in acetic acid (4 mL), ammonium acetate (20 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield 204 mg).

MS m/z 512 (M+H)⁺:

¹H NMR (CDCl₃): δ 7.68 (d, 2H), 7.23 (d, 2H), 7.19 (d, 2H), 7.13 (s, 1H), 7.04 (d, 2H), 6.97 (d, 2H), 6.87 (d, 2H) 4.04 (t, 2H), 2.88-2.96 (m, 8H), 2.36 (s, 3H), 2.12 (m, 2H), 1.59 (m, 2H), 1.23 (m, 2H), 1.18 (t, 6H), 0.83 (t, 3H) ppm

Example 495 [3-(4-{2-butyl-1-[4-(4-fluoro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 4-fluorophenol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into EtOAc (100 mL), washed with H₂O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-fluorophenoxy-1-nitrobenzene. The crude product may be used for further transformation.

The nitro intermediate (10 mmol) obtained above was dissolved in EtOAc (30 mL) and hydrogenated in the presence of 10% Pd/C (360 mg) until completion according to General Procedure H, as indicated by TLC or HPLC. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-fluorophenoxyaniline, which was used directly for further transformation without additional purification.

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added. The mesylate prepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched by treating the mixture with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated product was used for further transformation after purifying using silica gel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2.3 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.8 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a stirred solution of 4-fluorophenoxyaniline (1.2 eq., 2.5 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 7.5 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (2.3 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product obtained from 2-4% MeOH/DCM (yield ˜30%).

To a stirred solution of alkylated 4-fluorophenoxyaniline described above (0.8 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 2.4 mmol) was added, followed by slow addition of valeryl chloride (3 eq., 2.4 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the N-alkylated anilide (˜0.8 mmol) obtained as above in acetic acid (3 mL), solid ammonium acetate (16 mmol) was added in one portion, according to General Procedure R4. The reaction mixture was then heated to 100° C. overnight. The reaction mixture was cooled to rt, and treated with saturated aqueous sodium bicarbonate solution while stirring to until the pH was 7-8. The contents were extracted with EtOAc (2×15 mL). The combined organic layers was washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired N-aryl imidazole. The crude product was purified using silica gel column chromatography (2-5% MeOH/DCM) (yield 214 mg).

MS m/z 516 (M+H)⁺:

¹H NMR (CDCl₃): δ7.88 (d, 2H), 7.46 (d, 2H), 7.23 (d, 2H), 7.31 (s, 1H), 7.22 (d, 2H), 7.09 (d, 2H), 7.06 (d, 2H) 4.22 (t, 2H), 3.16 (m, 2H), 3.21 (q, 4H), 2.84 (t, 2H), 2.39-2.19 (m, 2H), 1.83 (m, 2H), 1.50 (m, 2H), 1.35 (t, 6H), 1.03 (t, 3H) ppm

Example 496 [3-(4-{2-butyl-1-[4-(4-chloro-3-ethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 4-chloro-3-ethylphenol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into EtOAc (100 mL), washed with H₂O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(4-chloro-3-ethylphenoxy)-1-nitrobenzene. The crude product was used for further transformation.

The nitro intermediate (10 mmol) obtained above was dissolved in MeOH (20 mL), and treated with SnCl₂.2H₂O (50 mmol), according to General Procedure I. The reaction mixture was heated under reflux until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo and the residue was treated with 4.0 N aqueous NaOH to pH ˜8. The residue was extracted with EtOAc (2×50 mL), washed with 1.0 N aqueous NaOH (50 mL), brine and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-chloro-3-ethylphenoxyaniline, which was used directly for further transformation without additional purification.

To a stirred solution of 4′-hydroxyacetophenone (91 mmol) in DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added. The mesylate prepared from 3-diethylamino-1-propanol and methanesulfonyl chloride (76 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched by treating the mixture with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (100 mL) and washed with H₂O (2×50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated product was used for further transformation after purifying using silica gel column chromatography (1-4% MeOH/DCM).

To a stirred solution of 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2.4 mmol) in anhydrous MeOH (5 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq., 2.9 mmol) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a stirred solution of 4-(4-chloro-3-ethylphenoxy)-1-nitrobenzene (1.2 eq., 2.5 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 7.5 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (2.4 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.

To a stirred solution of alkylated 4-(4-chloro-3-ethylphenoxy)-1-nitrobenzene described above (˜2.4 mmol) in anhydrous DCM (5 mL) at 0° C., TEA (3 eq., 7.5 mmol) was added, followed by slow addition of valeryl chloride (3 eq., 7.5 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the N-alkylated anilide (˜2.4 mmol) obtained as above in acetic acid (3 mL), solid ammonium acetate (46 mmol) was added in one portion, according to General Procedure R4. The reaction mixture was then heated to 100° C. overnight. The reaction mixture was cooled to rt, and treated with saturated aqueous sodium bicarbonate solution while stirring to until the pH was 7-8. The contents were extracted with EtOAc (2×30 mL). The combined organic layers was washed with H₂O (2×30 mL) and brine, and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired N-aryl imidazole. The crude product was purified using silica gel column chromatography (2-5% MeOH/DCM) (yield 60 mg).

MS m/z 560 (M+H)⁺:

¹H NMR (CDCl₃): δ8.30 (d, 1H), 7.64 (d, 2H), 7.28 (d, 2H), 7.21 (s, 1H), 7.18 (s, 1H), 7.03 (d, 2H), 6.90 (m, 1H), 6.83 (d, 2H) 4.22 (t, 2H), 2.85-2.75 (m, 2H), 2.89 (q, 4H), 2.61 (m, 2H), 2.24 (t, 2H), 2.14 (d, 3H), 2.09-1.98 (m, 2H), 1.58 (m, 2H), 1.28 (m, 2H), 1.25 (t, 6H), 0.93 (t, 3H) ppm.

Example 497 {2-[4-(2-butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-ethyl}-ethyl-amine

To a stirred solution of 4′-hydroxyacetophenone (4 mmol) in DMF (10 mL) at rt, solid potassium carbonate (12.0 mmol) was added. 4-chlorophenthoxy mesylate (prepwered from the 4-chlorophenethanol and methanesulfonyl chloride) (4.4 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (30 ml) and washed with water (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated product was purified by silica gel chromatography and the pure product obtained from 10% EtOAc/hexanes (yield 70%).

To a stirred solution of 4-fluoronitrobenzene (4.0 mmol) in anhydrous THF (12 mL) at 0° C., a 1M solution of a potassium alkoxide (4.4 mmol) in THF (may be generated by adding the N-Boc, N-ethyl ethanolamine to a 1M solution of KOBu^(t) in THF) was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. until completion, as indicated by TLC or HPLC. The solvent was removed and the reaction mixture was then treated with cold H₂O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The crude product could be used directly for further transformation.

The nitro intermediate (2 mmol) obtained above was dissolved in EtOH (8 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion, according to General Procedure H, as indicated by TLC or HPLC. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford 4-(N-Boc-N-ethylaminoethoxy)aniline, which was used directly for further transformation without further purification (yield 80%).

To a stirred solution of 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in anhydrous MeOH (6 mL) at 0° C., pyrrolidone hydrotribromide (1.2 eq) was added, according to General Procedure R1. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and was allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the crude 2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was used for further transformation.

To a solution of 4-(N-Boc-N-ethylethoxy)aniline (1 eq, 2 mmol) in anhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was added, followed by addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (2 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold water and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product obtained from 2-4% MeOH/DCM (yield 52%).

To a stirred solution of alkylated aniline described above (1 mmol) in anhydrous DCM (4 mL) at 0° C., TEA (3 eq, 3 mmol) was added, followed by a slow addition of valeryl chloride (3 eq, 3 mmol), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to rt until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (1 mmol) in acetic acid (4 mL), ammonium acetate (20 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the product imidazole, which was purified by column chromatography (Silica gel). Pure product obtained from 4-6% MeOH/DCM was treated with HCl in dioxane for 2 h to give the hydrochloride salt of {2-[4-(2-butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-ethyl}-ethyl-amine (yield 177 mg).

MS m/z 518 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ 7.7 (d, 2H), 7.2 (m, 4H), 7.1 (m, 3H), 6.8-7.0 (m, 4H), 4.0-4.3 (m, 6H), 3.0-3.2 (m, 6H), 2.9 (m, 2H), 2.6 (m, 2H), 1.2 (t, 3H), 0.8 (t, 3H) ppm

Example 498 [3-(4-{5-butyl-4-[4-(3,3-diphenyl-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-2,2-dimethyl-propyl]-dimethyl-amine

To a stirred solution of ice-cold 4-hydroxy-n-hexanophenone (18 mmol), 3,3-diphenyl-1-propanol (22.6 mmol, 1.25 eq), triphenylphosphine (22.6 mmol, 1.25 eq) dissolved in anhydrous THF (100 mL) was added dropwise diisopropyl azodicarboxylate (DIAD) (22.6 mmol, 1.25 eq). The reaction mixture was stirred at 0° C. for 1 h, and then allowed to warm to rt, continuing the stirring for additional 6 h (monitored by TLC). The solvent was removed in vacuuo, and the crude product was purified by silica gel column chromatography eluting with 10% EtOAc in hexane (yield: 100%).

The acetophone described as above (18 mmol) was dissolved in 1,4-dioxane (100 mL), and treated with pyridine hydrotribromide (18.9 mmol, 1.05 eq), according to General Procedure R1. After stirring at rt for 6 h (monitored by TLC), the reaction was quenched with cold H₂O (100 mL). The resulting mixture was extracted with EtOAc (4×100 mL). The combined EtOAc extracts were washed with brine (3×50 mL), and dried over anhydrous sodium sulfate. The solvent was then removed in vacuuo and the crude alpha-bromoacetophenone was directly used for further transformation.

To a stirred solution of the crude alpha-bromoacetophenone described as above (˜12 mmol) and 4-benzyloxyaniline (12 mmol) dissolved in DMF (40 mL), DIEA (36 mmol, 3 eq) was added at rt, and the mixture was stirred at the same temperature for 12 h, according to General Procedure R2 (monitored by TLC and LC-MS). The reaction mixture was treated with saturated sodium bicarbonate (100 mL), and the resulting mixture was extracted with EtOAc (4×100 mL). The combined EtOAc extracts were washed with brine (3×50 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude product was purified by silica gel column chromatography eluting with 10-15% EtOAc in hexane (overall yield from the acetophone: ˜50%).

To a stirred solution of ice-cold the alkylated aniline (1.7 mmol) obtained above and DMAP (3.4 mmol, 2 eq) dissolved in anhydrous DCM (200 mL), isovaleryl chloride (6.8 mmol, 4 eq) was added, according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 3 h and allowed to warm to rt until completion, as indicated by LC-MS. The solvent was removed in vacuuo, and the crude amide was used directly for further transformation.

The crude amide described above (˜3.7 mmol) was suspended in acetic acid (10 mL), and ammonium acetate (excess, ˜30 eq) was added, according to General Procedure R4. The reaction mixture was stirred at 120° C. for 20 h (as monitored by TLC and LC-MS). The reaction mixture was then cooled to rt and neutralized with saturated sodium bicarbonate and solid sodium carbonate. The resulting mixture was extracted with EtOAc (4×100 mL). The combined EtOAc extracts were washed with H₂O (2×60 mL) and brine (2×60 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the crude product was purified by silica gel column chromatography eluting with 10-20% EtOAc in hexane (overall yield from the alkylated aniline: 62%).

The product (2.9 mmol) obtained above was dissolved in MeOH (50 mL) and hydrogenated in the presence of 10% Pd/C (0.5 g) until completion as indicated by LC-MS (˜2 h), according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 1-(4′-hydroxyphenyl) imidazole, which was used directly for further transformation without purification (yield: 100%).

To a stirred solution of ice-cold 3-dimethylamino-2,2-dimethyl-1-propanol (1 mmol) and TEA (1.5 mmol) dissolved in anhydrous DCM (8 mmol) was added dropwise methanesulfonyl chloride (1.05 mmol), and the reaction mixture was stirred for 2 h at 0° C. and followed by additional 1 h at rt. After the removal of the solvents in vacuuo, the crude mesylate was dissolved in DMF (10 mL). 1-(4′-hydroxyphenyl) imidazole (0.5 mmol) obtained above and cesium carbonate (3 mmol) were added, and the mixture was heated with stirring at 90° C. for 3 h (monitored by LC-MS). After cooling to rt, the reaction was quenched with saturated sodium bicarbonate (20 mL), and the resulting mixture was extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with brine (3×30 mL), and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo, and the pure product was obtained by silica gel column chromatography eluting with 5-10% MeOH in EtOAc (yield 252 mg).

MS m/z 672 (M+H)⁺:

¹H NMR (400 MHz, CDCl₃): δ0.70 (t, 3H), 0.83 (d, 6H), 1.03 (s, 6H), 1.13 (m, 2H), 1.28 (m, 2H), 1.96 (m, 1H), 2.29 (s, 6H), 2.31 (s, 2H), 2.36 (d, 2H), 2.47-2.56 (m, 4H), 3.77 (s, 2H), 3.91 (t, 2H), 4.26 (t, 1H), 6.86 (d, 2H), 7.00 (d, 2H), 7.11 (d, 2H), 7.19-7.28 (m, 10H), 7.56 (d, 2H) ppm

Example 499 [3-(4-{4-[4-(3,3-diphenyl-propoxy)-phenyl]-2-isobutyl-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

To a stirred solution of N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq., 2.5 mmol) in anhydrous DMF (20 mL) DIEA (3 eq) was added, followed by slow addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone (2.5 mmol). The reaction mixture was stirred under nitrogen at rt until completion, as indicated by HPLC. The reaction mixture was then diluted with cold H₂O and the product was isolated in Et₂O. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained from 2-7% MeOH/DCM (yield ˜30%).

To a stirred solution of the alkylated aniline described above (0.88 mmol) in anhydrous DCM (10 mL) at 0° C., TEA (3.0 mmol) was added, followed by slow addition of isovaleryl chloride (5.0 eq), according to General Procedure R3. The reaction mixture was stirred under nitrogen at 0° C. for 1 h and allowed to warm to ambient temperature until completion, as indicated by HPLC. The solvent was removed in vacuuo, and the crude amide was used for further transformation.

To a stirred solution of the amide described above (0.88 mmol) in acetic acid (2 mL), ammonium acetate (excess, ˜20 eq.) was added, according to General Procedure R4. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was then cooled down and neutralized with saturated sodium bicarbonate solution. Usual extractive work up with EtOAc gave the cyclized product, (crude ˜80%) which was taken to the next transformation without purification.

The above product was dissolved in MeOH (20 mL), Pd/C (100 mg) was added and the heterogeneous mixture was stirred overnight under H₂ atmosphere using a balloon, according to General Procedure T2. The Pd/C was removed by filtration. The solvent was removed in vacuuo, and the crude 4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenol was used for further transformation without purification.

A stirred solution of the 4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenol (1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid sodium hydride (60% dispersion in oil; 1.0 mmol) in portions. The mesylate of 3,3-diphenylpropan-1-ol (1.1 eq) was added to the reaction mixture, and stirred at rt overnight, according to General Procedure T3. Et₂O (30 mL) was added to the reaction mixture followed by H₂O (10 mL). The organic layer was washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. The solvent was removed in vacuuo. Pure imidazole was obtained from chromatography with 5-10% MeOH/DCM (yield 73 mg).

MS m/z 616 (M+H)⁺:

¹H NMR (CDCl₃): δ7.67 (d, 2H), 7.15-7.3, (m, 12H), 7.09 (s, 1H), 6.96 (d, 2H), 6.84 (d, 2H), 4.25 (t, 1H), 4.07 (t, 2H), 3.9 (t, 2H), 3.74 (t, 1H), 2.46-2.75 (m, 10H), 2.0 (m, 3H), 1.0 (t, 6H), 0.84 (d, 6H) ppm.

Example 500 7-{2-butyl-4-[4-(4-chloro-phenoxy)-naphthalen-1-yl]-imidazol-1-yl}-1,2,3,4-tetrahydro-isoquinoline hydrochloride

7-Nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (8.2 g, 42% yield) was prepared by slightly modifying the published procedure (J. Med. Chem., 1997, 40, 3997-4005).

Di-tert-butyl dicarbonate (7.5 g, 33.8 mmol) was added to a solution of 7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.8 g, 16.9 mmol), Et₃N (9.42 mL, 67.6 mmol) and DMAP (0.1 g) dissolved in anhydrous THF (60 mL). After being stirred overnight at rt, the reaction mixture was treated with saturated NaHCO₃ (50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine and dried (Na₂SO₄). The crude products were purified by flash chromatography (eluting with 10-20% EtOAc in hexanes) to give 2-BOC-7-nitro-1,2,3,4-tetrahydroisoquinoline (4.1 g).

The nitro compound obtained above (4.1 g, 14.7 mmol) was dissolved in MeOH (80 mL) and hydrogenated in the presence of 10% Pd/C (0.3 g), according to General Procedure H. Workup afforded afforded 7-amino-2-Boc-1,2,3,4-tetrahydroisoquinoline (2-Boc-TIQ aniline (3.6 g, 98% yield) as a light-brown solid.

4′-(4-chlorophenoxy)-1′-acetonaphthone was prepared from 4′-fluoro-1′ acetonaphthone and 4-chlorophenol following general procedure Q2. 4′-(4-chlorophenoxy)-1′-acetonaphthone was brominated following general procedure R1. The bromo ketone was condensed with 7-amino-2-Boc-1,2,3,4-tetrahydroisoquinoline following general procedure R2. The aminoketone intermediate was treated with n-penatnoyl chloride according to general procedure R3. The product amide was then subjected to imidazole formation employing general procedure R4. The BOC group of the product was removed cmploying general procedure T1 to afford 7-{2-Butyl-4-[4-(4-chloro-phenoxy)-naphthalen-1-yl]-imidazol-1-yl}-1,2,3,4-tetrahydro-isoquinoline hydrochloride.

LC-MS (m/z): 508 (M+H)⁺.

Example 501 2-biphenyl-4-yl-N-{4-[2-butyl-1-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-1H-imidazol-4-yl]-phenyl}-acetamide hydrochloride

4-Nitrophenacyl bromide (5 mmol) was added to a stirred mixture of 2-BOC-7-nitro-1,2,3,4-tetrahydroisoquinoline (5 mmol) in DCM (20 mL) at rt, and the mixture was stirred at it overnight. The reaction mixture was treated with sat. NaHCO₃ (30 mL), the resulting mixture was extracted with EtOAc (200 mL), washed with brine and dried. The crude product was purified by silica gel column chromatography (eluting with 8% EtOAc in hexane to give the amino ketone intermediate (0.33 g).

Following the general procedures R2, R3, and R4 as for Example 500, the amino ketone intermediate (330 mg, 0.8 mmol) was converted into a 4-nitrophenyl-substituted imidazole. The imidazole was reduced by Pd-carbon catalytic hydrogenation following general procedure H to the corresponding 4-aminophenyl imidazole.

PS-carbodiimide (1.27 mmol/g, 310 mg, 0.4 mmol) was added to a mixture of the 4-aminophenyl imidazole obtained above (45 mg, 0.1 mmol) and biphenylacetic acid (43 mg, 0.2 mmol) in anhydrous DCM (6 mL), and the mixture was slowly shaken at rt overnight. The pure product (25 mg, 40% yield) was obtained after silica gel column chromatography (20% EtOAc in hexane). 2-Biphenyl-4-yl-N-{4-[2-butyl-1-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-1H-imidazol-4-yl]-phenyl}-acetamide hydrochloride (20 mg) was obtained by treating the product with 4N hydrogen chloride in dioxane solution, following the General Procedure T1.

LC-MS (m/z): 541 (M+1)⁺.

Example 502 7-{2-butyl-4-[4-(2,4-dichloro-phenoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-tetrahydro-isoquinoline hydrochloride

1-[4-(2,4-Dichlorophenoxy)phenyl]ethan-1-one (282 mg, 1 mmol) was brominated by General Procedure R1. The bromo ketone was condensed with 7-amino-2-Boc-1,2,3,4-tetrahydroisoquinoline following general procedure R2. The aminoketone intermediate was treated with n-penatnoyl chloride accoding to General Procedure R3. The product amide was then subjected to imidazole formation employing general procedure R4. The BOC group of the product was removed employing general procedure T1 to afford 7-{2-butyl-4-[4-(2,4-dichloro-phenoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-tetrahydro-isoquinoline hydrochloride (150 mg).

LC-MS (m/z): 493 (M+1)⁺.

Example 503 7-(2-butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-isobutyl-imidazol-1-yl)-1,2,3,4-tetrahydro-isoquinoline hydrochloride

1-[4-(4-chlorophenylethoxy)]ethan-1-one (1 mmol) was brominated by General Procedure R1. The bromo ketone was condensed with 7-amino-2-Boc-1,2,3,4-tetrahydroisoquinoline following general procedure R2. The aminoketone intermediate was treated with n-pentanoyl chloride accoding to General Procedure R3. The product amide was then subjected to imidazole formation employing general procedure R4. The BOC group of the product was removed employing general procedure T1 to afford 7-(2-Butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-isobutyl-imidazol-1-yl)-1,2,3,4-tetrahydro-isoquinoline hydrochloride (145 mg).

LC-MS (m/z): 486 (M+H)⁺.

Example 504 7-[4-(4-benzyloxy-phenyl)-2-butyl-imidazol-1-yl]-1,2,3,4-tetrahydro-isoquinoline hydrochloride

4-benzyloxyacetophone was brominated by General Procedure R1. The bromo ketone was condensed with 7-amino-2-Boc-1,2,3,4-tetrahydroisoquinoline following general procedure R2. The aminoketone intermediate was treated with n-pentanoyl chloride accoding to General Procedure R3. The product amide was then subjected to imidazole formation employing general procedure R4 to afford 7-[4-(4-Benzyloxy-phenyl)-2-butyl-imidazol-1-yl]-2-Boc-1,2,3,4-tetrahydro-isoquinoline. The BOC group of the product was removed employing general procedure T1 to afford 7-[4-(4-Benzyloxy-phenyl)-2-butyl-imidazol-1-yl]-1,2,3,4-tetrahydro-isoquinoline hydrochloride (170 mg).

LC-MS (m/z): 438 (M+1)⁺.

Example 505 9-(2-{4-[2-butyl-1-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-1H-imidazol-4-yl]-phenoxy}-ethyl-9H-carbazole hydrochloride

7-[4-(4-Benzyloxy-phenyl)-2-butyl-imidazol-1-yl]-2-Boc-1,2,3,4-tetrahydro-isoquinoline was debenzylated according to General Procedure T2 to afford 7-[4-(4-hydroxyphenyl)-2-butyl-imidazol-1-yl]-2-Boc-1,2,3,4-tetrahydro-isoquinoline. The phenol was condensed with the mesylate of 9H-carbazole-9-ethanol following general procedure T3 to afford the ethylcarbazole ether intermediate. This ethylcarbazole intermediate was deprotected employing general procedure T1 to afford 9-(2-{4-[2-butyl-1-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-1H-imidazol-4-yl]-phenoxy}-ethyl-9H-carbazole hydrochloride (55 mg).

LC-MS (m/z): 541 (M+1)⁺.

Example 506 7-{2-butyl-4-[4-(4-methoxy-phenoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-tetrahydro-isoquinoline hydrochloride

1-[4-(4-methoxyphenoxy)phenyl]ethan-1-one (1 mmol) was brominated by General Procedure R1. The bromo ketone was condensed with 7-amino-2-Boc-1,2,3,4-tetrahydroisoquinoline following general procedure R2. The aminoketone intermediate was treated with n-pentanoyl chloride accoding to General Procedure R3. The product amide was then subjected to imidazole formation employing general procedure R4. The BOC group of the product was removed employing general procedure T1 to afford 7-{2-butyl-4-[4-(4-methoxy-phenoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-tetrahydro-isoquinoline hydrochloride (yield 135 mg)

LC-MS (m/z): 454 (M+1)⁺.

Example 507 7-(2-butyl-4-{4-[2-(4-tert-butyl-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-1,2,3,4-tetrahydro-isoquinoline hydrochloride

7-[4-(4-hydroxyphenyl)-2-butyl-imidazol-1-yl]-2-Boc-1,2,3,4-tetrahydro-isoquinoline was condensed with the mesylate of 2-(4-t-butylphenyl)ethanol according to General Procedure T3 to afford the phenyl ether intermediate, which was deprotected according to general procedure T1 to afford 7-(2-butyl-4-{4-[2-(4-tert-butyl-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-1,2,3,4-tetrahydro-isoquinoline hydrochloride (35 mg).

LC-MS (m/z): 508 (M+1)⁺.

Example 508 7-{2-butyl-4-[4-(naphthalen-2-ylmethoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-tetrahydro-isoquinoline hydrochloride

7-[4-(4-hydroxyphenyl)-2-butyl-imidazol-1-yl]-2-Boc-1,2,3,4-tetrahydro-isoquinoline was condensed with 2-(bromomethyl)naphthalene according to general procedure T3 to afford the phenyl ether intermediate, which was deprotected according to general procedure T1 to afford 7-{2-butyl-4-[4-(naphthalen-2-ylmethoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-tetrahydro-isoquinoline hydrochloride (32 mg).

LC-MS (m/z): 488 (M+1)⁺.

Example 509 7-{2-butyl-4-[4-(4-trifluoromethyl-phenoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-tetrahydro-isoquinoline hydrochloride

7-[4-(4-hydroxyphenyl)-2-butyl-imidazol-1-yl]-2-Boc-1,2,3,4-tetrahydro-isoquinoline was condensed with 4-trifluoromethylbenzyl bromide according to general procedure T3 to afford the phenyl ether intermediate, which was deprotected according to general procedure T1 to afford 77-{2-butyl-4-[4-(4-trifluoromethyl-phenoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-tetrahydro-isoquinoline hydrochloride (45 mg).

LC-MS (m/z): 506 (M+1)⁺.

Example 510 7-(2-butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-1,2,3,4-tetrahydro-isoquinoline hydrochloride

1-[4-(4-chlorophenylethoxy)]ethan-1-one (1 mmol) was brominated by General Procedure R1. The bromo ketone was condensed with 7-amino-2-Boc-1,2,3,4-tetrahydroisoquinoline following general procedure R2. The aminoketone intermediate was treated with n-pentanoyl chloride accoding to General Procedure R3. The product amide was then subjected to imidazole formation employing general procedure R4. The BOC group of the product was removed employing general procedure T1 to afford 7-(2-Butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-1,2,3,4-tetrahydro-isoquinoline hydrochloride (170 mg).

LC-MS (m/z): 486 (M+1)⁺.

Example 511 [3-(4-{2-(4-Butyl-cyclohexyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

Example 511 was synthesized by the method established for Example 406, using 4-butylcyclohexanecarbonyl chloride in place of valeryl chloride (yield 300 mg).

MS: m/z 614 (M+H)⁺

Example 512 2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethylamine

Example 512 was synthesized by the method established for Example 464, utilizing N—BOC-ethanolamine in place of 3-dimethylamino-1-propanol to produce 2-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethylamino tert-butyl carbamate as an intermediate. This intermediate was deprotected employing general procedure T1 to afford Example 512 as the hydrochloride salt. (Yield: 115 mg).

MS: m/z 462 (M+H)⁺

Example 513 [3-(4-{2-(trans-4-tert-Butyl-cyclohexyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

Example 513 was prepared by chromatographic purification on silica gel of the compound of Example 486. 500 mg of Example 486 was separated by silica gel column chromatography, eluting with 5-10% MeOH in DCM, to give the cis-isomer (120 mg) followed by trans-isomer Example 513 (200 mg).

¹H NMR (400 MHz, CDCl₃): δ 0.82 (s, 9H), 1.08 (t, 6H), 1.50-2.50 (m, 12H), 2.66 (q, 4H), 2.73 (t, 2H), 4.02 (t, 2H), 6.89 (d, 2H), 7.04 (d, 2H), 7.07 (d, 2H), 7.08 (s, 1H), 7.27 (d, 2H), 7.36 (d, 2H), 7.69 (d, 2H) ppm

MS: m/z 614 (M+H)⁺

Example 514 [3-(4-{2-(cis-4-tert-Butyl-cyclohexyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

Example 514 was prepared by chromatographic purification on silica gel of the compound of Example 486. 500 mg of Example 486 was separated by silica gel column chromatography, eluting with 5-10% MeOH in DCM, to give the cis-isomer Example 514 (120 mg) followed by trans-isomer (200 mg).

MS: m/z 614 (M+H)⁺

Example 515 [2-(4-{2-Butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-ethyl]-methyl-pyridin-4-yl-amine

A mixture of 4-chloropyridine hydrochloride salt (15.0 g) and 2-methylaminoethanol (30 mL) was refluxed for 48 hour. After cooling to rt the crude mixture was added slowly to saturated solution of sodium bicarbonate (150 mL). The product was extracted with EtOAc (3×100 mL), the combined EtOAc was washed with brine (50 mL), dried (Na₂SO₄) and removed in vacuo to give the desired product 2-[methyl(pyridin-4-yl)amino]ethanol as yellow solid (7.0 g).

2-[methyl(pyridin-4-yl)amino]ethyl methanesulfonate was prepared according to general procedure P2.

4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazole-4-yl}-phenol was prepared via a modification of the procedure employed to synthesize {1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol.

Sodium hydride (50.0 mg, 60% dispersion in oil) was added to a mixture of 100 mg of 4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazole-4-yl}-phenol and 200 mg 2-[methyl(pyridin-4-yl)amino]ethyl methanesulfonate in DMF (5 mL). After 24 h of stirring at rt, the mixture was added to ether (50 mL) and the ether was washed with water and dried (Na₂SO₄). The solvent was removed in vacuo. Silica gel chromatography afforded 150 mg of Example 515.

MS: m/z 605 (M+H)⁺

Example 516 [2-(4-{1-[4-(4-Fluoro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethyl]-methyl-pyridin-4-yl-amine

4-{1-[4-(4-fluoro-phenoxy)-phenyl]-2-isobutyl-1H-imidazole-4-yl}phenol was prepared in analogous fashion to 4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazole-4-yl}phenol. Alkylation opf the phenol proceeded as for Example 515 to afford Example 516 (47 mg).

MS: m/z 537 (M+H)⁺

¹H NMR (CDCl₃): δ 8.23 (d, 2H), 7.70 (d, 2H), 7.53 (d, 2H,), 7.24 (s, 1H), 7.12 (d, 2H), 7.07 (m, 2H), 7.04 (d, 2H), 6.87 (d, 2H), 6.58 (d, 2H) 4.17 (t, 2H), 3.81 (t, 2H), 3.11 (s, 3H), 2.54 (d, 2H), 2.06 (m, 1H), 0.87 (d, 6H) ppm

Example 517 [2-(4-{1-[4-(4-Fluoro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethyl]-methyl-(3-methyl-pyridin-4-yl)-amine

Example 517 was prepared in analogous fashion to Example 516, with the use of 3-methyl-4-chloropyridine in place of 4-chloropyridine. (Yield: 110 mg)

MS: m/z 551 (M+H)⁺

Example 518 [2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethyl]-ethyl-pyridin-4-yl-amine

2-[Ethyl(pyridin-4-yl)amino]ethanol was synthesized via an analogous method as that employed for 2-[methyl(pyridin-4-yl)amino]ethanol.

2-[Ethyl(pyridin-4-yl)amino]ethanol was converted to the methanesulfonate via a modification of General Procedure P2.

{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol was synthesized by an analogous series of procedures as for Example 77.

Another procedure was below;

4-Acetoxyacetophenone (10.7 g, 60 mmol) in dioxane (200 mL) was treated with pyridinium hydrotribromide (21 g, 66 mmol, 1.1 eq) added in portions at rt, according to General Procedure R1. The reaction mixture was stirred at rt for 6 h. The reaction was quenched by adding cold H₂O (100 mL), and extracted with ether (4×100 mL). The ethereal solution was washed with H₂O (100 mL) and dried (anhydrous Na₂SO₄). The solvent was then removed in vacuo and the α-bromoacetophenone obtained above was added to a stirred solution of 4-(4′-chlorophenoxy)aniline (13.2 g, 60 mmol, 1.1 eq) and anhydrous DMF (100 mL) at rt, and the mixture was stirred at the same temperature for 5 h (monitored by LC-MS). The reaction mixture was treated with sat. NaHCO₃ (100 mL), and the resulting mixture was extracted with EtOAc (4×100 mL). The combined EtOAc extracts were washed with H₂O (2×100 mL) and brine (2×100 mL), and dried (Na₂SO₄). The solvent was removed in vacuo, and the alkylated aniline was used for next step

To a stirred solution of the c alkylated aniline dissolved in anhydrous DCM (250 mL) at 0° C., triethylamine (15.2 mL, 180 mmol) was added, followed by slow addition of isovaleryl chloride (14.7 mL, 120 mmol), according to General Procedure R3. The reaction mixture was stirred under N₂ at 0° C. for 0.5 h and then at rt for another 2 h (or monitored by LC-MS). The solvent was removed in vacuo, and the crude amide was used directly for further transformation.

To a stirred suspension of the amide described above in AcOH (30 mL), ammonium acetate (80 g) was added, according to General Procedure R4. The reaction mixture was stirred at 100° C. for 2 h (as monitored by LC-MS). The reaction mixture was then cooled down and neutralized with sat. NaHCO₃ (100 mL) and solid Na₂CO₃. The resulting mixture was extracted with EtOAc (4×150 mL) and the organic phase was concentrated. The light-yellow solid product was collected after filtration. The filtrate was concentrated in vacuo to about 150 mL volume and after standing at rt the solid product was collected and dried, overall yield 11 g of {1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol.

Sodium hydride (50.0 mg, 60% dispersion in oil) was added to mixture of 100 mg of 4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazole-4-yl}phenol and 180 mg of 2-[ethyl(pyridin-4-yl)amino]ethyl methanesulfonate in DMF (5 mL). After 24 h of stirring at rt, the mixture was added to ether (50 mL) and washed with water and dried (Na₂SO₄). The solvent was removed in vacuo. Chromatography on silica gel afforded Example 518 (36 mg).

MS: m/z 567 (M+H)⁺

Example 519 [2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethyl]-pyridin-4-yl-amine

2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethylamine, the product of Example 512, was treated with 4-chloropyridine in DMF and was heated at 100° C. Aqueous workup and chromatography on silica gel afforded Example 519. (Yield: 80 Mg)

MS: m/z 539 (M+H)⁺

Example 520 [2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethyl]-bis-pyridin-2-ylmethyl-amine

The methanesulfonate of N-Boc-glycinol was synthesized by modifying the general procedure P2.

{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol (2 mmol) was added to a solution of Cs₂CO₃ (10 eq., 20 mmol) in anhydrous DMF (5 ml). This was followed by addition of the mesylate obtained above and the reaction mixture was heated to 90° C. for 2-3 h. The reaction mixture was then cooled to rt, diluted with cold water and the product was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give desired product, which was BOC—deprotected according to general procedure T1. The HCl salt was dissolved in water, neutralized with 4N NaOH solution and the crude product was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give desired product amine.

The crude product obtained above was taken in anhydrous DCM (5 ml). 2-pyridylcarboxaldehyde (2.5 eq.) and Na(OAc)₃BH (2.5 eq.) was added to this solution and the reaction mixture was stirred at rt for 2-3 h. The product was concentrated in vacuo and extracted with EtOAc and the organic layer was washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give desired product, Example 520 (yield 96 mg).

MS: m/z 644 (M+H)⁺

Example 521 N-[2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethyl]-guanidine

2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethylamine, the product of Example 512, was treated in acetonitile with DIEA and N,N′-bis-BOC-1-guanylpyrazole. The resulting mixture was then refluxed. The reaction mixture was then cooled to rt and diluted with EtOAc. The mixture was washed with water and brine and dried over anhydrous sodium sulfate. Solvent was removed in vacuo and the residue obtained was purified by silica gel column chromatography to afford the BOC-protected guanadino intermediate. The BOC-protected guanadino intermediate was treated with 4M HCl/dioxane to remove the BOC group as described in general procedure T1, affording Example 521.

MS: m/z 504 (M+H)⁺

Example 522 2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-1-(4-pyridin-4-yl-piperazin-1-yl)-ethanone

To a stirred solution of 4-pyridyl-piperazine (2 mmol) in DCM (4 mL) at 0° C., triethylamine (6.0 mmol) was added followed by addition of 2-chloroacetyl chloride (4 mmol). The reaction mixture was stirred under nitrogen at it until completion, as indicated by TLC or HPLC. The reaction mixture was treated with saturated aqueous sodium bicarbonate solution (5 mL), then extracted with EtOAc (2×15 mL). The combined organic layers were washed with H₂O (2×15 mL) and brine, and dried over sodium sulfate. Evaporation of the solvent in vacuo afforded the amide. The crude product was used for further transformation.

To the above amide (2 mmol) in DMF (5 ml) was added Cesium carbonate (10 mmol, 5 eq), followed by the addition of {1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol (1.5 mmol) and the reaction was heated to 90° C. until completion, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was treated with saturated sodium bicarbonate (150 ml). The aqueous layer was extracted with EtOAc (4×100 ml). The organic layer was washed with water (2×10 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuo to afford the desired imidazole which was purified by was purified by chromatography over silica gel to afford Example 522.

MS: m/z 622 (M+H)⁺

Example 523 5-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxymethyl)-pyrrolidin-3-ol

Sodium borohydride (227 mg, 6 mmol) was added at 0° C. to a stirred solution of (2S,4R)—N—BOC-4-(t-butyldimethylsilyloxy)prolinaldehyde (522 mg, 1.58 mmol) in MeOH (10 mL), and the mixture was stirred at rt for 3 h. The reaction was quenched by adding sat. NaHCO₃ (20 mL), and the resulting mixture was extracted with EtOAc (3×50 mL). The EtOAc extracts were washed with brine (2×50 mL), and dried (Na₂SO₄). The solvent was removed in vacuo to give (2S,4R)—N—BOC-4-(t-butyldimethylsilylhydroxy)prolinol (550 mg).

The acohol obtained above was Converted to the methanesulfonate according to general procedure P2.

4-{1-[4-Chlorophenoxy)phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol described above (840 mg, 2 mmol) was added to a stirred mixture of the mesylate obtained in the previous step, Cs₂CO₃ (1.95 g, 6 mmol) in anhydrous DMF (20 mL), and the mixture was heated with stirring at 90° C. for 15 h. The reaction was quenched by adding sat. NaHCO₃ and the resulting mixture was extracted with EtOAc. The EtOAc extracts were washed with brine and dried (Na₂SO₄). The solvent was removed in vacuo to give crude alkylated product.

2N hydrogen chloride in ethereal solution (2 mL) was added to a stirred mixture of the alkylated imidazole obtained above (150 mg) in DCM (8 mL) at rt. After being stirred at rt for 4 h, the reaction mixture was treated with sat. NaHCO₃. The resulting mixture was extracted with EtOAc. The EtOAc extracts were washed with brine and dried (Na₂SO₄). The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography to give 5-(4-{1-[4-(4-chlorophenoxy)phenyl]-2-isobutyl-1H-imidazol-4-yl}phenoxymethyl)pyrrolidin-3-ol (50 mg).

LC-MS: m/z 518 (M+H)⁺

¹H NMR (400 MHz, CDCl₃): δ 0.84 (d, 6H), 1.25-3.20 (m, 6H), 2.53 (d, 2H), 4.05 (m, 3H), 4.50 (m, 1H), 6.91 (d, 2H), 7.01 (d, 2H), 7.05 (d, 2H), 7.10 (s, 1H), 7.24 (d, 2H), 7.34 (d, 2H), 7.66 (d, 2H) ppm.

Example 524 3-(4-{1-[4-(4-Fluoro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-pyridin-4-ylamine

To an ice-cold solution of 3-bromopyridine-N-oxide (4 mmol) in concentrated H₂SO₄ (4 ml), concentrated HNO₃ (0.5 ml) was added gradually. The reaction mixture was heated at 90° C. for 48 h. The reaction mixture was then cooled to rt, diluted with cold water and the product was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give desired product, 3-bromo-4-nitropyridine N-oxide.

{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol (1.1 eq. 4.4 mmol) was added slowly to a solution of NaH (8 mmol) in anhydrous DMF (6 ml) at 0° C. This was followed by addition of 3-bromo-4-nitropyridine-N-oxide (4 mmol) and the reaction mixture was heated to 90° C. for 2-3 h or until the completion of reaction. The reaction mixture was then cooled to rt, diluted with cold water and the product was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give desired product, which was taken up in acetic acid (4 ml). Powdered iron (2 eq., 8 mmol) was added and the reaction was heated to 90° C. for 2-3 h. The reaction mixture was then cooled to rt, diluted with cold water and the product was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give desired product, Example 524. (Yield: 60 mg)

MS: m/z 495 (M+1)⁺

Example 525 (4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenyl)-pyridin-4-yl-amine

[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-aniline was synthesized by procedures analogous to those for the similar 4-(4-aminophenyl)1H-imidazole intermediate in the preparation of Example 501.

A mixture of 200 mg of 4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazole-4-yl}aniline (200 mg, 0.47 mmole), 4-chloropyridine hydrochloride (0.5 g, 3.2 mmole) and potassium carbonate (0.5 g, 3.6 mmole) were heated at 100° C. in DMF (10 mL) for 24 h. After cooling to rt the mixture was diluted with ether, washed with water) and dried (Na₂SO₄). Silica gel chromatography of the crude material afforded Example 525 (50 mg).

MS: m/z 495 (M+H)⁺

Example 526 2-(4-{1-[4-(4-Fluoro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxymethyl)-3,5-dimethyl-pyridin-4-ylamine

(3,5-dimethyl-4-nitro-2-pyridyl)methyl mesylate was synthesized by the general procedure P2.

{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol (2 mmol) was added to a solution of Cs₂CO₃ (10 eq., 20 mmol) in anhydrous DMF (5 ml). This was followed by addition of the mesylate obtained above and the reaction mixture was heated to 90° C. for 2-3 h. The reaction mixture was then cooled to rt, diluted with cold water and the product was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give desired phenyl ether.

The crude product obtained above was taken in acetic acid (5 ml). Powdered iron (2 eq., 8 mmol) was added to the reaction mixture and the reaction was heated to 90° C. for 2-3 h or until the completion of reaction. The reaction mixture was then cooled to rt, diluted with cold water and the product was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give desired product. Example 526. (Yield: 80 mg)

MS: m/z 537 (M+H)⁺

Example 527 1-[2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethyl]-4-pyridin-4-yl-piperazine

The product of Example 522 was taken in 4 ml of THF to which was added 5 eq. of BH3-THF solution and the reaction was heated to reflux until the reaction was complete. The crude product was purified by silica gel chromatography to afford Example 527.

MS: m/z 608 (M+H)⁺

Example 528 4-(4-{2-Butyl-4-[4-(3-diethylamino-propoxy)-phenyl]-imidazol-1-yl}-phenoxy)-phenylamine

Example 528 was prepared by modifying the procedures utilized in the synthesis of Example 493, with utilization of 4-tert-butoxycarbonylaminophenol in place of 4-acetamidophenol. The BOC group was removed from the intermediate utilizing general procedure T1 to afford the product, Example 528, as the HCl salt.

MS: m/z 513 (M+H)⁺

Example 529 {3-[4-(2-Butyl-4-dibenzofuran-2-yl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

A solution of dibenzofuran (0.5 mmol) in anhydrous DCM was cooled to 0° C. AlCl₃ (1.5 eq., 0.75 mmol) was added followed by a slow addition of acetyl chloride (1.5 eq., 0.75 mmol). The reaction mixture was stirred at 0° C. for 2-3 h or until the completion of reaction. The product was extracted with DCM and washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concenterated in vacuo to give dibenzofuran-2-ylethan-2-one.

Example 529 was prepared by modifying the procedures utilized for the synthesis of Example 463, utilizing dibenzofuran-2-ylethan-2-one as the aryl ketone starting material. (Yield: 75 Mg)

MS: m/z 496 (M+H)⁺

Example 530 N-[4-(4-{2-Butyl-4-[4-(3-diethylamino-propoxy)-phenyl]-imidazol-1-yl}-phenoxy)-phenyl]-benzamide

Example 530 was prepared by modifying the procedures utilized in the synthesis of Example 493, with utilization of 4-(tert-butoxycarbonylamino)phenol in place of 4-acetamidophenol. The BOC group was removed from the intermediate utilizing general procedure T1 to afford the product, Example 528, as the HCl salt. The product was treated with benzoyl chloride and TEA in DCM to afford, after aqueous workup and purification by silica gel chromatography, Example 530.

MS: m/z 617 (M+H)⁺

Example 531 N-[4-(4-{2-Butyl-4-[4-(3-diethylamino-propoxy)-phenyl]-imidazol-1-yl}-phenoxy)-phenyl]-isonicotinamide

Example 530 was prepared by modifying the procedures utilized in the synthesis of Example 493, with utilization of 4-(tert-butoxycarbonylamino)phenol in place of 4-acetamidophenol. The BOC group was removed from the intermediate utilizing general procedure T1 to afford the product, Example 528, as the HCl salt. The product was treated with 4-pyridylcarbonyl chloride and TEA in DCM to afford, after aqueous workup and purification by silica gel chromatography, Example 531.

MS: m/z 618 (M+H)⁺

Example 532 [2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-ethyl]-methyl-pyridin-4-yl-amine

A mixture of 4-chloropyridine hydrochloride salt (15.0 g) and 2-methylaminoethanol (30 mL) was refluxed for 48 hour. After cooling to rt the crude mixture was added slowly to saturated solution of sodium bicarbonate (150 mL). The product was extracted with EtOAc (3×100 mL), the combined EtOAc was washed with brine (50 mL), dried (Na₂SO₄) and removed in vacuo to give the desired product 2-[methyl(pyridin-4-yl)amino]ethanol as yellow solid (7.0 g).

2-[methyl(pyridin-4-yl)amino]ethyl methanesulfonate was synthesized as described for Example 515.

Sodium hydride (50.0 mg, 60% dispersion in oil) was added to mixture of 150 mg of 4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazole-4-yl}phenol and 2-[methyl(pyridin-4-yl)amino]ethyl methanesulfonate (75 mg) in DMF (5 mL). After 24 h of stirring at rt, the mixture was added to ether (50 mL) and the organic phase was washed with water and dried (Na₂SO₄). The solvent was removed in vacuo and the product purified by silica gel chromatography to afford 80 mg of Example 532.

MS: m/z 553 (M+H)⁺

Example 533 N-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenyl)-2-dimethylamino-acetamide

1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-4-(4-nitrophenyl)-1H-imidazole was synthesized following the general procedures utilized in example 501. The nitro group was reduced according to general procedure H to afford 1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-4-(4-aminophenyl)-1H-imidazole, which was coupled with N,N-dimethylglycine using PS-carbodiimide according to the procedure utilized in Example 502 to afford Example 533.

MS: m/z 503 (M+H)⁺

Example 534 {3-[4-(4-{4-[3,3-Bis-(4-chloro-phenyl)-allyloxy]-phenyl}-2-isobutyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

Example 534 was synthesized by modification of the procedures utilized for the synthesis of example 459. 3,3(4-chlorophenyl)-2-propene-1-ol was converted to the methanesulfonate and utilized in condensation with 4′-hydroxyacetophenone. Isovaleryl chloride was utilized in place of benzyloxyacetyl chloride (yield 35 mg).

MS: m/z 682 (M+H)⁺

Example 535 {3-[4-(4-{-4-[3,3-Bis-(4-fluoro-phenyl)-propoxy]-phenyl}-2-isobutyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine

The intermediate phenol 4-(4-hydroxyphenyl)-2-isobutyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine utilized in the synthesis of Example 477 was condensed with the methanesulfonate of 3,3(4-fluorophenyl)-1-propanol (synthesized according to general procedure P2). The condensation was conducted in accord with similar operation in the preparation of Example 477 to provide Example 535.

MS: m/z 652 (M+H)⁺

Example 536 [2-(4-{4-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-imidazol-1-yl}-phenoxy)-ethyl]-methyl-pyridin-4-yl-amine

4-Fluoronitrobenzene was condensed with 2-[methyl(pyridin-4-yl)amino]ethanol according to general procedure C and the nitro group was then reduced according to general procedure H to afford the aniline intermediate. This aniline was utilized in modification of the procedure for preparation of Example 485 to afford Example 536.

MS: m/z 553 (M+H)⁺

Example 537 [3-(4-{4-{4-[2-(4-Chloro-phenyl)-ethoxy]-phenyl}-2-[2-(1-methyl-pyridin-3-yl)-ethyl]-imidazol-1-yl}-phenoxy)-propyl]-diethylmethyl aminonium iodide

{4-{4-[2-(4-Chloro-phenyl)-ethoxy]-phenyl}-2-[2-(pyridin-3-yl)-ethyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine was synthesized modifying the procedures utilized in the preparation of Example 485, where 3-(3-pyridyl)-propionyl chloride was utilized in place of valeryl chloride. The product {4-{4-[2-(4-Chloro-phenyl)-ethoxy]-phenyl}-2-[2-(pyridin-3-yl)-ethyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine was treated with excess methyl iodide, concentrated in vacuo, and the solid collected to afford the product, Example 537 (Yield: 37 mg)

MS: m/z 625 (M+H)⁺

Example 538 [3-(4-{2-(N—BOC-piperidine-4-ylmethyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

The procedure utilized for the preparation of Example 486 was modified, employing N—BOC-piperidine-4-acetic acid in place of 4-tert-butylcyclohexanecarboxylic acid, to afford 270 mg of Example 538.

MS: m/z 673 (M+H)⁺

Example 539 [3-(4-{2-(Piperidine-4-ylmethyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

The compound of Example 538 was deprotected according to General Procedure T1 to afford 116 mg of Example 539 as the HCl salt.

MS: m/z 573 (M+H)⁺

Example 540 [3-(4-{2-(N-ethyl-piperidine-4-ylmethyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine

[3-(4-{2-(Piperidine-4-ylmethyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine (Example 539) (0.1 mmol) was treated in anhydrous DCM (2 ml) with acetaldehyde (1.2 eq.,) followed by addition of Na(OAc)₃BH (1.5 eq.). The reaction mixture was stirred at rt. Crude product was extracted into EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concenterated in vacuo to give desired product, which was purified by column chromatography on silica gel to afford 49 mg of Example 540.

MS: m/z 601 (M+H)⁺

Example 541 [3-(4-{2-(piperidine-4-ylmethyl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

The procedure of Example 485 was adapted, using 4-BOC-piperidine-1-acetic acid in place of valeryl chloride. The resulting imidazole was deprotected using General Procedure T1 to afford Example 541 (48 mg) as the HCl salt.

MS: m/z 602 (M+H)⁺

Example 542 [3-(4-{2-(N-ethylpiperidine-4-ylmethyl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

The product of Example 541 was treated in anhydrous DCM (2 ml) with acetaldehyde (1.2 eq.,) followed by addition of Na(OAc)₃BH (1.5 eq.). The reaction mixture was stirred at rt. Crude product was extracted into EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concenterated in vacuo to give desired product, which was purified by column chromatography on silica gel to afford 50 mg of Example 542.

¹H NMR: δ 7.68 (d, 2H), 7.23 (m, 6H), 7.16 (s, 1H), 6.95 (m, 2H), 6.88 (d, 2H), 4.17 (t, 2H), 4.06 (t, 2H), 3.06 (t, 2H), 2.91 (d, 2H), 2.81 (broad, 1H), 2.57 (m, 6H), 2.43 (m, 6H), 1.95-2.05 (m, 6H), 1.09 (t, 9H) ppm

MS: m/z 629 (M+H)⁺

Example 543 [3-(4-{2-(N-acetylpiperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

The procedure of Example 485 was adapted, using 4-acetyl-piperidine-1-carbonyl chloride in place of valeryl chloride, to afford Example 543 (40 mg).

MS: m/z 629 (M+H)⁺

Example 544 [3-(4-{2-(piperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

Example 543 (1 mmol, 125 mg) was taken in 6 N HCl (5 ml) and the reaction was refluxed. The reaction mixture was then cooled to rt, diluted with water and neutralized with 3N NaOH solution. Product was extracted with EtOAc and the organic layer was dried over anhydrous sodium sulfate, concenterated in vacuo to give crude product, which was purified by column chromatography on silica gel to afford 290 mg of Example 544.

MS: m/z 587 (M+H)⁺

Example 545 [3-(4-{2-(N-Benzylpiperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

The product of Example 544 was treated in anhydrous DCM (2 ml) with benzaldehyde (1.2 eq.,) followed by addition of Na(OAc)₃BH (1.5 eq.). The reaction mixture was stirred at rt. Crude product was extracted into EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concenterated in vacuo to give desired product, which was purified by column chromatography on silica gel to afford 50 mg of Example 545.

¹H NMR: δ 7.68 (d, 2H), 7.28 (d, 2H), 7.21-7.26 (m, 9H), 7.17 (s, 1H), 6.97 (d, 2H), 6.87 (d, 2H), 4.16 (t, 2H), 4.07 (t, 2H), 3.48 (s, 2H), 3.05 (t, 2H), 2.91 (broad, 1H), 2.74 (t, 2H), 2.66 (m, 8H), 2.05 (m, 6H), 1.11 (t, 6H) ppm

MS: m/z 677 (M+H)⁺

Example 546 [3-(4-{2-(N-(2-Pyridylmethyl)piperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

The product of Example 544 was treated in anhydrous DCM (2 ml) with pyridine-2-carboxaldehyde (1.2 eq.,) followed by addition of Na(OAc)₃BH (1.5 eq.). The reaction mixture was stirred at rt. Crude product was extracted into EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give desired product, which was purified by column chromatography on silica gel to afford 40 mg of Example 546.

MS: m/z 678 (M+H)⁺

Example 547 [3-(4-{2-(N-(2-Imidazolylmethyl)piperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

The product of Example 544 was treated in anhydrous DCM (2 ml) with imidazole-2-carboxaldehyde (1.2 eq.,) followed by addition of Na(OAc)₃BH (1.5 eq.). The reaction mixture was stirred at rt. Crude product was extracted into EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give desired product, which was purified by column chromatography on silica gel to afford 40 mg of Example 547.

¹H NMR: δ 7.66 (d, 2H), 7.2-7.3 (m, 7H), 7.06 (s, 1H), 6.98 (m, 3H), 6.88 (d, 2H), 4.18 (t, 2H), 4.05 (t, 2H), 3.65 (s, 2H), 3.08 (t, 2H), 2.81 (broad, 1H), 2.75 (m, 2H), 2.55-2.65 (m, 8H), 1.95-2.08 (m, 6H), 1.09 (t, 6H) ppm

MS: m/z 667 (M+H)⁺

Example 548 [3-(4-{2-(N-(4-biphenyl)methylpiperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

The product of Example 544 was treated in anhydrous DCM (2 ml) with 4-biphenylcarboxaldehyde (1.2 eq.,) followed by addition of Na(OAc)₃BH (1.5 eq.). The reaction mixture was stirred at rt. Crude product was extracted into EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give desired product, which was purified by column chromatography on silica gel to afford 45 mg of Example 548.

¹H NMR: δ 7.68 (d, 2H), 7.59 (d, 2H), 7.54 (d, 2H), 7.38-7.44 (m, 5H), 7.19-7.29 (m, 6H), 7.09 (s, 1H), 6.79 (d, 2H), 6.88 (d, 2H), 4.18 (t, 2H), 4.08 (t, 2H), 3.55 (s, 2H), 3.08 (t, 2H), 2.98 (broad, 1H), 2.65 (t, 2H), 2.58-2.65 (m, 8H), 1.98-2.09 (m, 6H), 1.12 (t, 6H) ppm.

MS: m/z 753 (M+H)⁺

Example 549 [3-(4-{2-(N-Cyclohexylpiperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

The product of Example 544 was treated in anhydrous DCM (2 ml) with cyclopentanone (1.2 eq.,) followed by addition of Na(OAc)₃BH (1.5 eq.). The reaction mixture was stirred at rt. Crude product was extracted into EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give desired product, which was purified by column chromatography on silica gel to afford 52 mg of Example 549.

¹H NMR: δ 7.68 (d, 2H), 7.38 (m, 3H), 7.21 (m, 3H), 7.08 (s, 1H), 6.98 (m, 2H), 6.88 (d, 2H), 4.18 (t, 2H), 4.08 (t, 2H), 3.08 (t, 2H), 2.67 (t, 2H), 2.51-2.55 (m, 8H), 1.99-2.08 (m, 6H), 1.91 (broad, 4H), 1.68 (broad 2H), 1.51 (broad 4H), 1.12 (t, 6H) ppm.

MS: m/z 655 (M+H)⁺

Example 550 [3-(4-{2-(N-(4-Cyanobenzyl)piperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

The product of Example 544 was treated in anhydrous DCM (2 ml) with 4-cyanobenzaldehyde (1.2 eq.,) followed by addition of Na(OAc)₃BH (1.5 eq.). The reaction mixture was stirred at rt. Crude product was extracted into EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give desired product, which was purified by column chromatography on silica gel to afford 70 mg of Example 550.

¹H NMR: δ 7.69 (d, 2H), 7.59 (d, 2H), 7.44 (d, 2H), 7.2-7.3 (m, 6H), 7.09 (s, 1H), 6.99 (d, 2H), 6.88 (d, 2H), 4.18 (t, 2H), 4.09 (t, 2H), 3.55 (s, 2H), 3.08 (t, 2H), 2.85 (broad, 1H), 2.5-2.8 (m, 10H), 1.9-2.1 (m, 6H), 1.09 (t, 6H) ppm.

MS: m/z 702 (M+H)⁺

Example 551 [3-(4-{2-(N-Ethylpiperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine

The product of Example 544 was treated in anhydrous DCM (2 ml) with acetaldehyde (1.2 eq.,) followed by addition of Na(OAc)₃BH (1.5 eq.). The reaction mixture was stirred at rt. Crude product was extracted into EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give desired product, which was purified by column chromatography on silica gel to afford 50 mg of Example 551.

¹H NMR: δ 7.68 (d, 2H), 7.23 (d, 2H), 7.22 (m, 4H), 7.16 (s, 1H), 6.95 (d, 2H), 6.88 (d, 2H), 4.17 (t, 2H), 4.05 (t, 2H), 3.05-3.07 (m, 7H), 2.51-2.61 (m, 6H), 2.39 (q, 2H), 1.89-2.09 (m, 6H), 1.12 (t, 9H) ppm.

MS: m/z 678 (M+H)⁺

Biological Assay

The following assay method is utilized to identify compounds of Formula (I) which are effective in binding with RAGE, and hence useful as modulators, preferably antagonists of RAGE.

General Assay Procedure

S100b, β-amyloid and CML (500 ng/100 μL/well) in 100 mM sodium bicarbonate/sodium carbonate buffer (pH 9.8) is loaded onto the wells of a NUNC Maxisorp flat bottom 96-well microtitre plate. The plate is incubated at 4° C. overnight. The wells are aspirated and treated with 50 mM imidazole buffer saline (pH 7.2) (with 5 mM CaCl₂/MgCl₂) containing 1% bovine serum albumin (BSA) (300 μL/well) for 1 h at RT. The wells are aspirated.

Test compounds are dissolved in nanopure water (concentration: 10-100 μM). DMSO may be used as co-solvent. 25 μL of test compound solution in 4% DMSO is added, along with 75 μL sRAGE (6.75 nM FAC) to each well and samples are incubated for 1 h at 37° C. The wells are washed 4 times with 155 mM NaCl pH 7.2 buffer saline and are soaked 10 seconds between each wash.

Non-radioactive detection is performed by adding:

10 μL Biotinylated goat F(ab′)2 Anti-mouse IgG. (8.0×10⁻⁴ mg/mL, FAC)

5 μL Alk-phos-Sterptavidin (3×10⁻³ mg/mL FAC)

0.42 μL per 5 mL Monoclonal antibody for sRAGE (FAC 6.0×10⁻³ mg/mL)

to 5 mL 50 mM imidazole buffer saline (pH 7.2) containing 0.2% bovine serum albumin and 5 mM CaCl₂. The mixture is incubated for 30 minutes at RT. 100 μL complex is added to each well and incubation is allowed to proceed at rt for 1 h. Wells are washed 4 times with wash buffer and soaked 10 s between each wash. 100 μL 1 mg/mL (pNPP) in 1 M diethanolamine (pH adjusted to 9.8 with HCl) is added. Color is allowed to develop in the dark for 30 min to 1 h at rt. The reaction is quenched with 10 μL of stop solution (0.5 N NaOH in 50% ethanol) and the absorbance is measured spectrophotometrically with a microplate reader at 405 nm.

The Examples in Table 1 were tested according to the assay method described above, employing S100b as the RAGE ligand, and were found to possess IC₅₀ in the assay of less than 10 μM. IC₅₀ (μM) of ELISA assay represents the concentration of compound at which 50% signal has been inhibited.

The invention further provides pharmaceutical compositions comprising the RAGE modulating compounds of the invention. The term “pharmaceutical composition” is used herein to denote a composition that may be administered to a mammalian host, e.g., orally, topically, parenterally, by inhalation spray, or rectally, in unit dosage formulations containing conventional non-toxic carriers, diluents, adjuvants, vehicles and the like. The term “parenteral” as used herein, includes subcutaneous injections, intravenous, intramuscular, intracisternal injection, or by infusion techniques.

The pharmaceutical compositions containing a compound of the invention may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous, or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically-acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Pat. Nos. 4,356,108; 4,166,452; and 4,265,874, incorporated herein by reference, to form osmotic therapeutic tablets for controlled release.

Formulations for oral use may also be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or a soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions may contain the active compounds in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyl-eneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil of coconut oil, or in a mineral oil such as a liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alchol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring, and coloring agents may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example a liquid paraffin, or a mixture thereof. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectible aqueous or oleaginous suspension. This suspension may be formulated according to the known methods using suitable dispersing or wetting agents and suspending agents described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conveniently employed as solvent or suspending medium. For this purpose, any bland fixed oil may be employed using synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compositions may also be in the form of suppositories for rectal administration of the compounds of the invention. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols, for example.

For topical use, creams, ointments, jellies, solutions or suspensions, lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols etc., containing the compounds of the invention are contemplated. These topical formulations may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams. The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 0.1% up to about 99% of the formulation. More usually they will form up to about 80% of the formulation. For the purpose of this application, topical applications shall include mouth washes and gargles.

The compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes may be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. Also provided by the present invention are prodrugs of the invention.

For administration by inhalation the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.

Pharmaceutically acceptable salts of the compounds of the present invention, where a basic or acidic group is present in the structure, are also included within the scope of the invention. The term “pharmaceutically acceptable salts” refers to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base. Representative salts include the following salts: Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrocloride, Hydroxynaphthoate, Iodide, Isethionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methyliodide, Methylchloride, Methylnitrate, Methylsulfate, Monopotassium Maleate, Mucate, Napsylate, Nitrate, N-methylglucamine, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate, Polygalacturonate, Potassium, Salicylate, Sodium, Stearate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide, Trimethylammonium and Valerate. When an acidic substituent is present, such as —COOH, there can be formed the ammonium, morpholinium, sodium, potassium, barium, calcium salt, and the like, for use as the dosage form. When a basic group is present, such as amino or a basic heteroaryl radical, such as pyridyl, an acidic salt, such as hydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate, trichloroacetate, acetate, oxlate, maleate, pyruvate, malonate, succinate, citrate, tartarate, fumarate, mandelate, benzoate, cinnamate, methiodide, methbromide, methchloride, methanesulfonate, ethanesulfonate, picrate and the like, and include acids related to the pharmaceutically-acceptable salts listed in the Journal of Pharmaceutical Science, 66, 2 (1977) p. 1-19.

Other salts which are not pharmaceutically acceptable may be useful in the preparation of compounds of the invention and these form a further aspect of the invention.

In addition, some of the compounds of the present invention may form solvates with water or common organic solvents. Such solvates are also encompassed within the scope of the invention.

Thus, in a further embodiment, there is provided a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents.

The compounds of the present invention selectively act as modulators of RAGE binding to a single endogenous ligand, i.e., selective modulators of β-amyloid—RAGE interaction, and therefore are especially advantageous in treatment of Alzheimer's disease and related dementias.

Further, the compounds of the present invention act as modulators of RAGE interaction with two or more endogenous ligands in preference to others. Such compounds are advantageous in treatment of related or unrelated pathologies mediated by RAGE, i.e., Alzheimer's disease and cancer.

Further, the compounds of the present invention act as modulators of RAGE binding to each and every one of its ligands, thereby preventing the generation of oxidative stress and activation of NF-κB regulated genes, such as the cytokines IL-1, and TNF-α. Thus, antagonizing the binding of physiological ligands to RAGE prevent targeted pathophysiological consequences and useful for management or treatment of diseases, i.e., AGE-RAGE interaction leading to diabetic complications, S100/EN-RAGE/calgranulin-RAGE interaction leading to inflammatory diseases, β-amyloid-RAGE interaction leading to Alzheimer's Disease, and amphoterin-RAGE interaction leading to cancer.

I. RAGE and the Complications of Diabetes

As noted above, the compounds of the present invention are useful in the treatment of the complications of diabetes. It has been shown that nonenzymatic glycoxidation of macromolecules ultimately resulting in the formation of advanced glycation endproducts (AGEs) is enhanced at sites of inflammation, in renal failure, in the presence of hyperglycemia and other conditions associated with systemic or local oxidant stress (Dyer, D., et al., J. Clin. Invest., 91:2463-2469 (1993); Reddy, S., et al., Biochem., 34:10872-10878 (1995); Dyer, D., et al., J. Biol. Chem., 266:11654-11660 (1991); Degenhardt, T., et al., Cell Mot Biol., 44:1139-1145 (1998)). Accumulation of AGEs in the vasculature can occur focally, as in the joint amyloid composed of AGE-β₂-microglobulin found in patients with dialysis-related amyloidosis (Miyata, T., et al., J. Clin. Invest., 92:1243-1252 (1993); Miyata, T., et al., J. Clin. Invest, 98:1088-1094 (1996)), or generally, as exemplified by the vasculature and tissues of patients with diabetes (Schmidt, A-M., et al., Nature Med., 1:1002-1004 (1995)). The progressive accumulation of AGEs over time in patients with diabetes suggests that endogenous clearance mechanisms are not able to function effectively at sites of AGE deposition. Such accumulated AGEs have the capacity to alter cellular properties by a number of mechanisms. Although RAGE is expressed at low levels in normal tissues and vasculature, in an environment where the receptor's ligands accumulate, it has been shown that RAGE becomes upregulated (Li, J. et al., J. Biol. Chem., 272:16498-16506 (1997); Li, J., et al., J. Biol. Chem., 273:30870-30878 (1998); Tanaka, N., et al., J. Biol. Chem., 275:25781-25790 (2000)). RAGE expression is increased in endothelium, smooth muscle cells and infiltrating mononuclear phagocytes in diabetic vasculature. Also, studies in cell culture have demonstrated that AGE-RAGE interaction caused changes in cellular properties important in vascular homeostasis.

II. RAGE and Cellular Dysfunction in the Amyloidoses

Also as noted above, the compounds of the present invention are useful in treating amyloidoses and Alzheimer's disease. RAGE appears to be a cell surface receptor which binds β-sheet fibrillar material regardless of the composition of the subunits (amyloid-β peptide, Aβ, amylin, serum amyloid A, prion-derived peptide) (Yan, S.-D., et al., Nature, 382:685-691 (1996); Yan, S-D., et al., Nat. Med., 6:643-651 (2000)). Deposition of amyloid has been shown to result in enhanced expression of RAGE. For example, in the brains of patients with Alzheimer's disease (AD), RAGE expression increases in neurons and glia (Yan, S.-D., et al., Nature 382:685-691 (1996)). The consequences of Aβ interaction with RAGE appear to be quite different on neurons versus microglia. Whereas microglia become activated as a consequence of Aβ-RAGE interaction, as reflected by increased motility and expression of cytokines, early RAGE-mediated neuronal activation is superceded by cytotoxicity at later times.

Further evidence of a role for RAGE in cellular interactions of Aβ concerns inhibition of Aβ-induced cerebral vasoconstriction and transfer of the peptide across the blood-brain barrier to brain parenchyma when the receptor was blocked (Kumar, S., et al., Neurosci. Program, p 141-#275.19 (2000)). Inhibition of RAGE-amyloid interaction has been shown to decrease expression of cellular RAGE and cell stress markers (as well as NF-kB activation), and diminish amyloid deposition (Yan, S-D., et al., Nat. Med., 6:643-651 (2000)) suggesting a role for RAGE-amyloid interaction in both perturbation of cellular properties in an environment enriched for amyloid (even at early stages) as well as in amyloid accumulation.

III. RAGE and Propagation of the Immune/Inflammatory Response

As noted above, the compounds of the present invention are useful in treating inflammation. For example, S100/calgranulins have been shown to comprise a family of closely related calcium-binding polypeptides characterized by two EF-hand regions linked by a connecting peptide (Schafer, B. et al., TIBS, 21:134-140 (1996); Zimmer, D., et al., Brain Res. Bull., 37:417-429 (1995); Rammes, A., et al., J. Biol. Chem., 272:9496-9502 (1997); Lugering, N., et al., Eur. J. Clin. Invest., 25:659-664 (1995)). Although they lack signal peptides, it has long been known that S100/calgranulins gain access to the extracellular space, especially at sites of chronic immune/inflammatory responses, as in cystic fibrosis and rheumatoid arthritis. RAGE is a receptor for many members of the S100/calgranulin family, mediating their proinflammatory effects on cells such as lymphocytes and mononuclear phagocytes. Also, studies on delayed-type hypersensitivity response, colitis in IL-10 null mice, collagen-induced arthritis, and experimental autoimmune encephalitis models suggest that RAGE-ligand interaction (presumably with S100/calgranulins) has a proximal role in the inflammatory cascade as implicated in the inflammatory diseases such as but not limited to rheumatoid arthritis and multiple sclerosis.

RAGE is also implicated in inflammatory diseases of the skin such as but not limited to atopic dermatitis, eczema, and psoriasis. Psoriasis in particular is characterized by inflamed itchy lesions. Psoriasis may be accompanied by arthropathic symptoms that are similar to those in seen in rheumatoid arthritis.

There is considerable evidence that psoriasis is a polygenic autoimmune disorder. Psoriatic lesions are rich in cytokines, in particular IL-1 and IL-8, both potent proinflammatory mediators. IL-8 in particular is a chemotactic factor for neutrophils; neutrophils are also known to synthesize and secrete S100 proteins, one of the ligands for RAGE which is implicated in propogation of the immune and inflammatory response. Psoriasin (S100A7) a new member of the S100 gene family, is a secreted protein isolated from psoriatic skin. Semprini et. al. (Hum. Genet. 2002 October, 111(4-5), 310-3) have shown a linkage of psoriasis genetic susceptibility to distinct overexpression of S100 proteins in skin. Therefore, a modulator of RAGE would be expected to regulate the immune response in psoriasis.

IV. RAGE and Amphoterin

As noted above, the compounds of the present invention are useful in treating tumor and tumor metastasis. For example, amphoterin is a high mobility group I nonhistone chromosomal DNA binding protein (Rauvala, H., at al., J. Biol. Chem., 262:16625-16635 (1987); Parkikinen, J., et al., J. Biol. Chem. 268:19726-19738 (1993)) which has been shown to interact with RAGE. It has been shown that amphoterin promotes neurite outgrowth, as well as serving as a surface for assembly of protease complexes in the fibrinolytic system (also known to contribute to cell mobility). In addition, a local tumor growth inhibitory effect of blocking RAGE has been observed in a primary tumor model (C6 glioma), the Lewis lung metastasis model (Taguchi, A., et al., Nature 405:354-360 (2000)), and spontaneously arising papillomas in mice expressing the v-Ha-ras transgene (Leder, A., et al., Proc. Natl. Acad. Sci., 87:9178-9182 (1990)).

Amphoterin is a high mobility group I nonhistone chromosomal DNA binding protein (Rauvala, H. and R. Pihlaskari. 1987. Isolation and some characteristics of an adhesive factor of brain that enhances neurite outgrowth in central neurons. J. Biol. Chem. 262:16625-16635. (Parkikinen, J., E. Raulo, J. Merenmies, R. Nolo, E. Kajander, M. Baumann, and H. Rauvala. 1993. Amphoterin, the 30 kDa protein in a family of HIMG1-type polypeptides. J. Biol. Chem. 268:19 726-19738).

V. RAGE and Erectile Dysfunction

Relaxation of the smooth muscle cells in the cavernosal arterioles and sinuses results in increased blood flow into the penis, raising corpus cavernosum pressure to culminate in penile erection. Nitric oxide is considered the principle stimulator of cavernosal smooth muscle relaxation (See Wingard C J, Clinton W, Branam H, Stopper V S, Lewis R W, Mills T M, Chitaley K. Antagonism of Rho-kinase stimulates rat penile erection via a nitric oxide-independent pathway. Nature Medicine 2001 January; 7(1):119-122). RAGE activation produces oxidants (See Yan, S-D., Schmidt A-M., Anderson, G., Zhang, J., Brett, J., Zou, Y-S., Pinsky, D., and Stern, D. Enhanced cellular oxidant stress by the interaction of advanced glycation endproducts with their receptors/binding proteins. J. Biol. Chem. 269:9889-9887, 1994.) via an NADH oxidase-like enzyme, therefore suppressing the circulation of nitric oxide. Potentially by inhibiting the activation of RAGE signaling pathways by decreasing the intracellular production of AGEs, generation of oxidants will be attenuated. RAGE blockers may promote and facilitate penile erection by blocking the access of ligands to RAGE.

The calcium-sensitizing Rho-kinase pathway may play a synergistic role in cavernosal vasoconstriction to maintain penile flaccidity. The antagonism of Rho-kinase results in increased corpus cavernosum pressure, initiating the erectile response independently of nitric oxide (Wingard et al.). One of the signaling mechanisms activated by RAGE involves the Rho-kinase family such as cdc42 and rac (See Huttunen H J, Fages C, Rauvala H. Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-kappaB require the cytoplasmic domain of the receptor but different downstream signaling pathways. J Biol Chem 1999 Jul. 9; 274(28):19919-24). Thus, inhibiting activation of Rho-kinases via suppression of RAGE signaling pathways will enhance and stimulate penile erection independently of nitric oxide.

VI. RAGE and Respiratory Diseases

Airway inflammation is important in the pathogenesis of asthma. Such inflammation may give rise to significant exacerbations and increases in asthma severity, as well as to be a major factor in a decline in asthmatic status. In severe exacerbations of asthma there is an intense, mechanistically heterogeneous inflammatory response involving neutrophil and eosinophil accumulation and activation. Neutrophils are a significant source of S100 proteins, key ligands for RAGE implicated in the propogation of the immune response and inflammation. Therefore, modulators of RAGE would be expected to possess therapeutic value in the treatment of asthma.

Further, the propogation step in the immune response in the lung driven by S100—RAGE interaction would be expected to lead to the activation and/or recruitment of inflammatory cells, such as neutrophils, which in chronic obstructive pulmonary diseases such as emphysema, are significant sources of damaging proteases. Therefore, a RAGE modulator would be expected possess potential in the treatment of chronic obstructive pulmonary diseases.

Thus, in a further aspect, the present invention provides a method for the inhibition of the interaction of RAGE with physiological ligands. In a preferred embodiment of this aspect, the present invention provides a method for treating a disease state selected from the group consisting of acute and chronic inflammationin cluding but not limited to skin inflammation such as psoriasis nad atopic dermatitis and lung inflammation including asthma and chronic osbtructive pulmonary disease, vascular permeability, nephropathy, atherosclerosis, retinopathy, Alzheimer's disease, erectile dysfunction, and tumor invasion and/or metastasis, which comprises administering to a subject in need thereof a compound of the present invention, preferably a pharmacologically effective amount, more preferably a therapeutically effective amount. In a preferred embodiment, at least one compound of Formula (I) is utilized, either alone or in combination with one or more known therapeutic agents. In a further preferred embodiment, the present invention provides method of prevention and/or treatment of RAGE mediated human diseases, treatment comprising alleviation of one or more symptoms resulting from that disorder, to an outright cure for that particular disorder or prevention of the onset of the disorder, the method comprising administration to a human in need thereof a therapeutically effective amount of a compound of the present invention, preferably a compound of Formula (I).

In this method, factors which will influence what constitutes an effective amount will depend upon the size and weight of the subject, the biodegradability of the therapeutic agent, the activity of the therapeutic agent, as well as its bioavailability. As used herein, the phrase “a subject in need thereof” includes mammalian subjects, preferably humans, who either suffer from one or more of the aforesaid diseases or disease states or are at risk for such. Accordingly, in the context of the therapeutic method of the invention, this method also is comprised of a method for treating a mammalian subject prophylactically, or prior to the onset of diagnosis such disease(s) or disease state(s).

In a further aspect of the present invention, the RAGE modulators of the invention are utilized in adjuvant therapeutic or combination therapeutic treatments with other known therapeutic agents.

The term “treatment” as used herein, refers to the full spectrum of treatments for a given disorder from which the patient is suffering, including alleviation of one, most of all symptoms resulting from that disorder, to an outright cure for the particular disorder or prevention of the onset of the disorder.

The following is a non-exhaustive listing of adjuvants and additional therapeutic agents which may be utilized in combination with the RAGE modulators of the present invention:

Pharmacologic classifications of anticancer agents:

-   1. Alkylating agents: Cyclophosphamide, nitrosoureas, carboplatin,     cisplatin, procarbazine -   2. Antibiotics: Bleomycin, Daunorubicin, Doxorubicin -   3. Antimetabolites: Methotrexate, Cytarabine, Fluorouracil -   4. Plant alkaloids: Vinblastine, Vincristine, Etoposide, Paclitaxel, -   5. Hormones: Tamoxifen, Octreotide acetate, Finasteride, Flutamide -   6. Biologic response modifiers: Interferons, Interleukins,     Anti-tumor antibodies

Pharmacologic classifications of treatment for Rheumatoid Arthritis (Inflammation)

-   1. Analgesics: Aspirin -   2. NSAIDs (Nonsteroidal anti-inflammatory drugs): Ibuprofen,     Naproxen, Diclofenac -   3. DMARDs (Disease-Modifying Antirheumatic drugs): Methotrexate,     gold preparations, hydroxychloroquine, sulfasalazine -   4. Biologic Response Modifiers, DMARDs: Etanercept, Infliximab     Glucocorticoids

Pharmacologic classifications of treatment for Diabetes Mellitus

-   Sulfonylureas: Tolbutamide, Tolazamide, Glyburide, Glipizide -   2. Biguanides: Metformin -   3. Miscellaneous oral agents: Acarbose, Troglitazone -   4. Insulin

Pharmacologic classifications of treatment for Alzheimer's Disease

-   1. Cholinesterase Inhibitor: Tacrine, Donepezil -   2. Antipsychotics: Haloperidol, Thioridazine -   3. Antidepressants: Desipramine, Fluoxetine, Trazodone, Paroxetine -   4. Anticonvulsants: Carbamazepine, Valproic acid

In a further preferred embodiment, the present invention provides a method of treating RAGE mediated diseases, the method comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula (I) in combination with therapeutic agents selected from the group consisting of alkylating agents, antimetabolites, plant alkaloids, antibiotics, hormones, biologic response modifiers, analgesics, NSAIDs, DMARDs, glucocorticoids, sulfonylureas, biguanides, insulin, cholinesterase inhibitors, antipsychotics, antidepressants, and anticonvulsants. In a further preferred embodiment, the present invention provides the pharmaceutical composition of the invention as described above, further comprising one or more therapeutic agents selected from the group consisting of alkylating agents, antimetabolites, plant alkaloids, antibiotics, hormones, biologic response modifiers, analgesics, NSAIDs, DMARDs, glucocorticoids, sulfonylureas, biguanides, insulin, cholinesterase inhibitors, antipsychotics, antidepressants, and anticonvulsants.

Generally speaking, the compound of the present invention, preferably Formula (I), is administered at a dosage level of from about 0.01 to 500 mg/kg of the body weight of the subject being treated systemically, with a preferred dosage range between 0.01 and 200 mg/kg, most preferably 0.1 to 100 mg/kg of body weight per day. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may contain 1 mg to 2 grams of a compound of Formula (I) with an appropriate and convenient amount of carrier material which may vary from about 5 to 95 percent of the total composition. Also a dosage form intended for topical administration to the skin may be prepared at 0.1% to 99% compound to topical excipient ratio and a dosage form intended for inhaled administration of 0.01 to 200 mg of compound in a suitable carrier to deliver an inhaled dosage of compound. Dosage unit forms of systemically delivered compound will generally contain between from about 5 mg to about 500 mg of active ingredient. This dosage has to be individualized by the clinician based on the specific clinical condition of the subject being treated. Thus, it will be understood that the specific dosage level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

While the invention has been described and illustrated with reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the preferred dosages as set forth herein may be applicable as a consequence of variations in the responsiveness of the mammal being treated for RAGE-mediated disease(s). Likewise, the specific pharmacological responses observed may vary according to and depending on the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. 

1. A method for prevention and/or treatment of a RAGE mediated human disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I):

wherein R₁ is -hydrogen, -alkyl, -alkenyl, or -alkynyl, A₁ is —N(R₂)—, wherein R₂ is -phenyl, R₃ is a) -hydrogen, b)-halogen, c) -hydroxyl, d)-cyano, e) -carbamoyl, f) -carboxyl, g) -aryl, h) -cycloalkyl, i) -alkyl, j) -alkenyl, k) -alkynyl, l) -alkylene-aryl, m) -alkylene-cycloalkyl, n) -fused cycloalkylaryl, o) -alkylene-fused cycloalkylaryl, p) —C(O)—O-alkyl, q) —C(O)—O-alkylene-aryl, r) —C(O)—NH-alkyl, s) —C(O)—NH-alkylene-aryl, t) —SO₂-alkyl, u) —SO₂-alkylene-aryl, v) —SO₂-aryl, w) —SO₂—NH-alkyl, x) —SO₂—NH-alkylene-aryl, y) —C(O)-alkyl, z) —C(O)-alkylene-aryl, aa) -G₄-G₅-G₆-R₇, bb) —Y₁-alkyl, cc) —Y₁-aryl, dd) —Y₁-alkylene-aryl, ee) —Y₁-alkylene-NR₉R₁₀, or ff) —Y₁-alkylene-W₁—R₁₁, wherein G₄ and G₆ are independently selected from the group consisting of: alkylene, alkenylene, alkynylene, cycloalkylene, arylene, -alkylene-aryl, -alkenylene-aryl, -alkenylene-heteroaryl, and a direct bond; G₅ is —O—, —S—, —N(R₈)—, —S(O)—, —S(O)₂—, —C(O)—, —O—C(O)—, —C(O)—O—, —C(O)N(R₈)—, N(R₈)C(O)—, —S(O₂)N(R₈)—, N(R₈)S(O₂)—, —O-alkylene-C(O)—, —(O)C-alkylene-O—, —O-alkylene-, -alkylene-O—, alkylene, alkenylene, alkynylene, cycloalkylene, arylene, fused cycloalkylarylene, or a direct bond, wherein R₈ is -hydrogen, -aryl, -alkyl, -alkylene-aryl, or -alkylene-O-aryl; R₇ is -hydrogen, -aryl, -cycloalkyl, -alkyl, -alkenyl, -alkynyl, -alkylene-aryl, -alkylene-cycloalkyl, -fused cycloalkylaryl, or -alkylene-fused cycloalkylaryl; Y₁ and W₁ are independently selected from the group consisting of —CH₂—, —O—, —N(H), —S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—CO—,

wherein R₁₂ and R₁₃ are independently selected from the group consisting of: -aryl, -alkyl, -alkylene-aryl, alkoxy, and -alkylene-O-aryl; and R₉, R₁₀, and R₁₁ are independently selected from the group consisting of: -aryl, -alkyl, and -alkylene-aryl; R₄ is a) -phenyl, b) -phenylene-G₅-G₆-R₇, c) -phenylene-alkylene-G₅-G₆-R₇, or d) -phenylene-alkylenylene-G₅-G₆-R₇, wherein G₆ is alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene, heteroarylene, -alkylene-aryl, -alkylene-heteroaryl, alkenylene-aryl, -alkenylene-heteroaryl, or a direct bond; G₅ is —O—, —S—, —N(R₈)—, —S(O)—, —S(O)₂—, —C(O)—, —O—C(O)—, —C(O)—O—, —C(O)N(R₈)—, N(R₈)C(O)—, —S(O₂)N(R₈)—, N(R₈)S(O₂)—, —O-alkylene-C(O)—, —(O)C-alkylene-O—, —O-alkylene-, -alkylene-O—, alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene, heteroarylene, fused cycloalkylarylene, fused cycloalkylheteroarylene, fused heterocyclylarylene, fused heterocyclylheteroarylene, or a direct bond, wherein R₈ is -hydrogen, -aryl, -alkyl, -alkylene-aryl, or -alkylene-O-aryl; R₇ is hydrogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkyl, alkenyl, alkynyl, alkylene-aryl, -alkylene-heteroaryl, -alkylene-heterocyclyl, -alkylene-cycloalkyl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl, fused heterocyclylheteroaryl, alkylene-fused cycloalkylaryl, -alkylene-fused cycloalkylheteroaryl, -alkylene-fused heterocyclylaryl, or -alkylene-fused heterocyclylheteroaryl; wherein the aryl and/or alkyl group(s) in R₃, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, and R₁₃, may be optionally substituted 1-4 times with a substituent group, wherein said substituent group(s) are independently selected from the group consisting of: a) —H, b) -halogen, c) -hydroxyl, d) -cyano, e) -carbamoyl, f) -carboxyl, g) —Y₂-alkyl, h) —Y₂-aryl, i) —Y₂-alkylene-aryl j) —Y₂-alkylene-W₂—R₁₈, k) —Y₃—Y₄—NR₂₃R₂₄, l) —Y₃—Y₄—NH—C(═NR₂₅)NR₂₃R₂₄, and m) —Y₃—Y₄—C(═NR₂₅)NR₂₃R₂₄, wherein Y₂ and W₂ is —CH₂—, —O—, —N(H), —S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—S(O)₂—, —O—CO—,

 wherein;  R₁₉ and R₂₀ are independently selected from the group consisting of: -hydrogen, -aryl, -alkyl, -alkylene-aryl, -alkoxy, and -alkylene-O-aryl; R₁₈ is -aryl, -alkyl, -alkylene-aryl, or -alkylene-O-aryl; Y₃ is selected from the group consisting of a direct bond, —CH₂—, —O—, —N(H), —S—, SO₂—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—CO—,

 wherein R₂₇ and R₂₈ are independently selected from the group consisting of: -aryl, -alkyl, -alkylene-aryl, alkoxy, and -alkyl-O-aryl; Y₄ is  a) -alkylene,  b) -alkenylene,  c) -alkynylene,  d) -arylene,  e) -cycloalkylene,  f) -alkylene-arylene,  g) -alkylene-cycloalkylene,  h)-arylene-alkylene,  i)-cycloalkylene-alkylene,  j) —O—,  k) —S—,  l) —S(O₂)—, or  m) —S(O)—,  wherein said alkylene groups may optionally contain one or more O, S, S(O), or SO₂ atoms; and R₂₃, R₂₄, and R₂₅ are independently selected from the group consisting of: -hydrogen, -aryl, -alkyl, -alkylene-aryl, and -alkylene-O-aryl, and wherein R₂ may be optionally substituted 1-4 times with a substituent group, wherein said substituent group(s) are independently selected from the group consisting of: a) —H, b) -halogen, c) -hydroxyl, d) -cyano, e) -carbamoyl, f) -carboxyl, g) —Y₂-alkyl, h) —Y₂-aryl, i) —Y₂-heteroaryl, j) —Y₂-alkylene-heteroaryl-aryl, k) —Y₂-alkylene-aryl, l) —Y₂-alkylene-W₂—R₁₅, m) —Y₃—Y₄—NR₂₃R₂₄, n) —Y₃—Y₄—NH—C(═NR₂₅)NR₂₃R₂₄, o) —Y₃—Y₄—C(═NR₂₅)NR₂₃R₂₄, and p) —Y₃—Y₄—Y₅-A₂ wherein Y₂ and W₂ are independently selected from the group consisting of —CH₂—, —O—, —N(H), —S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—S(O)₂—, —O—CO—,

wherein;  R₁₉ and R₂₀ are independently selected from the group consisting of: -hydrogen, -aryl, -alkyl, -alkylene-aryl, -alkoxy, and -alkylene-O-aryl; R₁₈ is -aryl, -alkyl, -alkylene-aryl, -alkylene-heteroaryl, or -alkylene-O-aryl; Y₃ and Y₅ are independently selected from the and consisting of a direct bond, —CH₂—, —O—, —N(H), —S—, SO₂—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—CO—,

wherein R₂₇ and R₂₆ are independently selected from the group consisting of: -aryl, -alkyl, -alkylene-aryl, alkoxy, and -alkyl-O-aryl; Y₄ is a) -alkylene, b) -alkenylene, c) -alkynylene, d) -arylene, e) -heteroarylene, f) -cycloalkylene, g) -heterocyclylene, h) -alkylene-arylene, i) -alkylene-heteroarylene, j) -alkylene-cycloalkylene, k) -alkylene-heterocyclylene, l) -arylene-alkylene, m) -heteroarylene-alkylene, n) -cycloalkylene-alkylene, o) -heterocyclylene-alkylene, p) —O—, q) —S—, r) —S(O₂)—, or s) —S(O)—,  wherein said alkylene groups may optionally contain one or more O, S, S(O), or SO₂ atoms; A₂ is a) heterocyclyl, fused arylheterocyclyl, or fused heteroarylheterocyclyl, containing at least one basic nitrogen atom, or b) -imidazolyl, and R₂₃, R₂₄, and R₂₅ are independently selected from the group consisting of: -hydrogen, -aryl, -heteroaryl, -alkylene-heteroaryl, -alkyl, -alkylene-aryl, -alkylene-O-aryl, and -alkylene-O-heteroaryl; and R₂₃ and R₂₄ may be taken together to form a five-membered ring having the formula —(CH₂)_(s)—X₃—(CH₂)_(t)— bonded to the nitrogen atom to which R₂₃ and R₂₄ are attached wherein  s and t are, independently, 1, 2, 3, or 4;  X₃ is a direct bond, —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

 wherein R₂₈ and R₂₉ are independently selected from the group consisting of: -hydrogen, -aryl, -heteroaryl, -alkyl, -alkylene-aryl, and -alkylene-heteroaryl; wherein the alkyl and/or aryl groups in the optional substituents a) —Y₂-alkyl, b) —Y₂-aryl, c) —Y₂-heteroaryl, d) —Y₂-alyklene-heteroaryl, e) —Y₂-alkylene-aryl, f) —Y₂-alkylene-W₂—R₁₈, g) —Y₃—Y₄—NR₂₃R₂₄, h) —Y₃—Y₄—NH—C(═NR₂₅)NR₂₃R₂₄, i) Y₃—Y₄—C(═NR₂₅)NR₂₃R₂₄, and j) —Y₃—Y₄—Y₅-A₂, of R₂ may be optionally substituted 1-4 times with a substitutent independently selected from the group consisting of:  a) halogen,  b) perhaloalkyl,  c) alkyl,  d) cyano,  e) alkyloxy,  f) aryl, and  g) aryloxy, and wherein the aryl and/or alkyl group(s) in R₄ may be optionally substituted 1-4 times with a substituent group, wherein said substituent group(s) are independently selected from the group consisting of: a) —H, b) -halogen, c) -hydroxyl, d) -cyano, e) -carbamoyl, f) -carboxyl, g) —Y₂-alkyl, h) —Y₂-aryl, i) —Y₂-heteroaryl, j) —Y₂-alkylene-heteroaryl-aryl, k) —Y₂-alkylene-aryl, l) —Y₂-alkylene-W₂—R₁₈, m) —Y₃—Y₄—NR₂₃R₂₄, n) —Y₃—Y₄—NH—C(═NR₂₅)NR₂₃R₂₄, o) —Y₃—Y₄—C(═NR₂₅)NR₂₃R₂₄, and P) —Y₃—Y₄—Y₅-A₂, wherein Y₂ and W₂ are independently selected from the group consisting of —CH₂—, —O—, —N(H), —S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—S(O)₂—, —O—CO—,

wherein  R₁₉ and R₂₀ are independently selected from the group consisting of: -hydrogen, -aryl, -alkyl, -alkylene-aryl, -alkoxy, and -alkylene-O-aryl; R₁₈ is -aryl, -alkyl, -alkylene-aryl, -alkylene-heteroaryl, or -alkylene-O-aryl; Y₃ and Y₅ are independently selected from the group consisting of a direct bond, —CH₂—, —O—, —N(H), —S—, SO₂—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—CO—,

wherein R₂₇ and R₂₆ are independently selected from the group consisting of: -aryl, -alkyl, -alkylene-aryl, -alkoxy, and -alkyl-O-aryl; Y₄ is a) -alkylene, b) -alkenylene, c) -alkynylene, d) -arylene, e) -heteroarylene, f) -cycloalkylene, g) -heterocyclylene, h) -alkylene-arylene, i) -alkylene-heteroarylene, j) -alkylene-cycloalkylene, k) -alkylene-heterocyclylene, l) -arylene-alkylene, m) -heteroarylene-alkylene, n) -cycloalkylene-alkylene, o) -heterocyclylene-alkylene, p) —O—, q) —S—, r) —S(O₂)—, or s) —S(O)—,  wherein said alkylene groups may optionally contain one or more O, S, S(O), or SO₂ atoms; A₂ is a) heterocyclyl, fused arylheterocyclyl, or fused heteroarylheterocyclyl, containing at least one basic nitrogen atom, or b) -imidazolyl, and R₂₃, R₂₄, and R₂₅ are independently selected from the group consisting of: -hydrogen, -aryl, -heteroaryl, -alkylene-heteroaryl, -alkyl, -alkylene-aryl, -alkylene-O-aryl, and -alkylene-O-heteroaryl; and R₂₃ and R₂₄ may be taken together to form a five-membered ring having the formula —(CH₂)_(s)—X₃—(CH₂)_(t)— bonded to the nitrogen atom to which R₂₃ and R₂₄ are attached wherein  s and t are, independently, 1, 2, 3, or 4;  X₃ is a direct bond, —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

 wherein R₂₈ and R₂₉ are independently selected from the group consisting of: -hydrogen, -aryl, -heteroaryl, -alkyl, -alkylene-aryl, and -alkylene-heteroaryl; wherein the alkyl and/or aryl groups in the optional substituents a) —Y₂-alkyl, b) —Y₂-aryl, c) —Y₂-heteroaryl, d) —Y₂-alkylene-heteroaryl, e) —Y₂-alkylene-aryl, f) —Y₂-alkylene-W₂—R₁₈, g) —Y₃—Y₄—NR₂₃R₂₄, h) —Y₃—Y₄—NH—C(═NR₂₅)NR₂₃R₂₄, i) —Y₃—Y₄—C(═NR₂₅)NR₂₃R₂₄, and j) —Y₃—Y₄—Y₅-A₂, of R₂ and R₄ may be optionally substituted 1-4 times with a substitutent independently selected from the group consisting of:  a) halogen,  b) perhaloalkyl,  c) alkyl,  d) cyano,  e) alkyloxy,  f) aryl, and  g) aryloxy, and wherein the ring or rings containing a heteroatom in the heteroaryl, heteroarylene, heterocyclyl, heterocyclene, fused arylheterocyclyl, or fused heteroarylheterocyclyl groups in R₂ or R₄ or in a substituent of R₂ or R₄ is a five-membered nitrogen containing ring, and wherein at least one of R₂ and R₄ is substituted with at least one group of the formula a) —Y₃—Y₄—NR₂₃R₂₄, b) —Y₃—Y₄—NH—C(═NR₂₅)NR₂₃R₂₄, c) Y₃—Y₄—C(═NR₂₅)NR₂₃R₂₄, or d) —Y₃—Y₄—Y₅-A₂, with the proviso that no more than one of R₂₃, R₂₄, and R₂₅ is aryl or heteroaryl; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 2. The method according to claim 1 for treatment of acute and/or chronic systemic inflammation which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 3. The method according to claim 1 for treatment of acute and/or chronic skin inflammation which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 4. The method according to claim 1 for treatment of vascular permeability which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 5. The method according to claim 1 for treatment of nephropathy which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 6. The method according to claim 1 for treatment of atherosclerosis which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 7. The method according to claim 1 for treatment of retinopathy which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 8. The method according to claim 1 for treatment of asthma which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 9. The method according to claim 1 for treatment of chronic obstructive pulmonary disease which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 10. A method for prevention and/or treatment of a RAGE mediated human disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ib):

wherein R₁ is -hydrogen, -alkyl, or -alkenyl, R₃ is -hydrogen or -alkyl, and R₁₀₂ and R₁₀₄ are independently selected from the group consisting of: a) —H, b) -alkyl, c) -aryl, d) -heteroaryl, e) -alkylene-heteroaryl-aryl, f) -alkylene-aryl, g) -alkylene-W₂—R₁₈, h) —Y₄—NR₂₃R₂₄, i) —Y₄—NH—C(═NR₂₅)NR₂₃R₂₄, j) —Y₄—C(═NR₂₅)NR₂₃R₂₄, and k) —Y₄—Y₅-A₂; wherein W₂ is —CH₂—, —O—, —N(H), —S—, SO₂—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—S(O)₂—, —O—CO—,

 wherein R₁₉ and R₂₀ are independently selected from the group consisting of: -hydrogen, -aryl, -alkyl, -alkylene-aryl, -alkoxy, and -alkylene-O-aryl; R₁₈ is -aryl, -alkyl, -alkylene-aryl, -alkylene-heteroaryl, or -alkylene-O-aryl; Y₅ is a direct bond, —CH₂—, —O—, —N(H), —S—, SO₂—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —NHSO₂NH—, —O—CO—,

 wherein R₂₇ and R₂₆ are independently selected from the group consisting of -aryl, -alkyl, -alkylene-aryl, -alkoxy, and -alkyl-O-aryl; Y₄ is  a) -alkylene,  b) -alkenylene,  c) -alkynylene,  d) -arylene,  e) -heteroarylene,  f) -cycloalkylene,  g) -heterocyclylene,  h) -alkylene-arylene,  i) -alkylene-heteroarylene,  j) -alkylene-cycloalkylene,  k)-alkylene-heterocyclylene,  l) -arylene-alkylene,  m) -heteroarylene-alkylene,  n) -cycloalkylene-alkylene,  o) -heterocyclylene-alkylene,  p) —O—,  q) —S—,  r) —S(O₂)—, or  s) —S(O)—;  wherein said alkylene groups may optionally contain one or more O, S, S(O), or SO₂ atoms; A₂ is  a) heterocyclyl, fused arylheterocyclyl, or fused heteroarylheterocyclyl, containing at least one basic nitrogen atom, or  b) -imidazolyl, R₂₃, R₂₄, and R₂₅ are independently selected from the group consisting of: -hydrogen, -aryl, -heteroaryl, -alkylene-heteroaryl, -alkyl, -alkylene-aryl, -alkylene-O-aryl, and -alkylene-O-heteroaryl; and R₂₃ and R₂₄ may be taken together to form a five-membered ring having the formula —(CH₂)_(s)—X₃—(CH₂)_(t)— bonded to the nitrogen atom to which R₂₃ and R₂₄ are attached  wherein  a and t are, independently, 1, 2, 3, or 4;  X₃ is a direct bond, —CH₂—, —O—, —S—, —S(O₂)—, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

 wherein R₂₅ and R₂₉ are independently selected from the group consisting of: -hydrogen, -aryl, -heteroaryl, -alkyl, -alkylene-aryl, and -alkylene-heteroaryl; wherein the alkyl and/or aryl groups of R₁₀₂ and R₁₀₄ may be optionally substituted 1-4 times with a substituent group selected from the group consisting of: a) halogen, b) perhaloalkyl, c) alkyl, d) cyano, e) alkyloxy, f) aryl, and g) aryloxy wherein the ring or rings containing a heteroatom in the heteroaryl, heterarylene, heterocyclyl, heterocyclene, fused arylheterocyclyl, or fused heteroarylheterocyclyl groups in R₁₀₂ or R₁₀₄ or in a substituent of R₁₀₂ or R₁₀₄ is a five-membered nitrogen containing ring, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 11. The method according to claim 10 for treatment of acute and/or chronic system inflammation which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 12. The method according to claim 10 for treatment of acute and/or chronic skin inflammation which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 13. The method according to claim 10 for treatment of vascular permeability which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 14. The method according to claim 10 for treatment of nephropathy which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 15. The method according to claim 10 for treatment of atherosclerosis which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 16. The method according to claim 10 for treatment of retinopathy which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 17. The method according to claim 10 for treatment of asthma which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 18. The method according to claim 10 for treatment of chronic obstructive pulmonary disease which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 19. A method for prevention and/or treatment of a RAGE mediated human disease comprising administering to a subject in need thereof a therapeutically effective amount of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 20. The method according to claim 19 for treatment of acute and/or chronic systemic inflammation which comprises administering to a subject in need thereof a therapeutically effective amount of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 21. The method according to claim 19 for treatment of acute and/or chronic skin inflammation which comprises administering to a subject in need thereof a therapeutically effective amount of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 22. The method according to claim 19 for treatment of acute vascular permeability which comprises administering to a subject in need thereof a therapeutically effective amount of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 23. The method according to claim 19 for treatment of nephropathy which comprises administering to a subject in need thereof a therapeutically effective amount of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 24. The method according to claim 19 for treatment of atherosclerosis which comprises administering to a subject in need thereof a therapeutically effective amount of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 25. The method according to claim 19 for treatment of retinopathy which comprises administering to a subject in need thereof a therapeutically effective amount of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 26. The method according to claim 19 for treatment of asthma which comprises administering to a subject in need thereof a therapeutically effective amount of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 27. The method according to claim 19 for treatment of chronic obstructive pulmonary disease which comprises administering to a subject in need thereof a therapeutically effective amount of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 